Thanks to visit codestin.com
Credit goes to link.springer.com

Skip to main content
Springer Nature Link
Log in

The coming-of-age of nucleocytoplasmic transport in motor neuron disease and neurodegeneration

  • Review
  • Published:
Cellular and Molecular Life Sciences Aims and scope Submit manuscript

A Correction to this article was published on 28 March 2019

This article has been updated

Abstract

The nuclear pore is the gatekeeper of nucleocytoplasmic transport and signaling through which a vast flux of information is continuously exchanged between the nuclear and cytoplasmic compartments to maintain cellular homeostasis. A unifying and organizing principle has recently emerged that cements the notion that several forms of amyotrophic lateral sclerosis (ALS), and growing number of other neurodegenerative diseases, co-opt the dysregulation of nucleocytoplasmic transport and that this impairment is a pathogenic driver of neurodegeneration. The understanding of shared pathomechanisms that underpin neurodegenerative diseases with impairments in nucleocytoplasmic transport and how these interface with current concepts of nucleocytoplasmic transport is bound to illuminate this fundamental biological process in a yet more physiological context. Here, I summarize unresolved questions and evidence and extend basic and critical concepts and challenges of nucleocytoplasmic transport and its role in the pathogenesis of neurodegenerative diseases, such as ALS. These principles will help to appreciate the roles of nucleocytoplasmic transport in the pathogenesis of ALS and other neurodegenerative diseases, and generate a framework for new ideas of the susceptibility of motoneurons, and possibly other neurons, to degeneration by dysregulation of nucleocytoplasmic transport.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Subscribe and save

Springer+
from £29.99 /Month
  • Starting from 10 chapters or articles per month
  • Access and download chapters and articles from more than 300k books and 2,500 journals
  • Cancel anytime
View plans

Buy Now

Price includes VAT (United Kingdom)

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3
Fig. 4

Image adapted from reference [255]

Similar content being viewed by others

Explore related subjects

Discover the latest articles, books and news in related subjects, suggested using machine learning.

Change history

  • 28 March 2019

    The original version of this article unfortunately contained the following misspelling and formatting mistakes.

Abbreviations

ALS :

Amyotrophic lateral sclerosis

Ranbp2 :

Ran-binding protein 2

Ranbp1 :

Ran-binding protein 1

RBDs :

Ran-GTP-binding domains

ZnF :

Zinc-finger motif

Nup:

Nucleoporin

CY:

Cyclophilin

RCC1 :

Regulator of chromosome condensation 1

RanGAP1 :

Ran GTPase-activating protein-1

NTRs :

Nuclear transport receptors

NES :

Nuclear export sequence

NLS :

Nuclear localization sequence

mRNP :

Messenger ribonucleoprotein

TREX :

Transcription–export complex,

hnRNPs :

Heterogeneous nuclear ribonucleoproteins

CBC :

Cap-binding complex

EJC :

Exon-junction complex

eIF :

Eukaryotic initiation factor

SRP :

Signal recognition particle

SSCR :

Signal sequence-coding region

ALREX :

Alternative mRNA nuclear export

Cxcl14 :

Chemokine ligand 14

Acc1 :

Acetyl-CoA carboxylase 1

SOD1 :

Cu/Zn Superoxide dismutase 1,

C9ORF72 :

Chromosome 9 Open Reading Frame 72

TARDBP :

Transactive response DNA-binding protein (TDP-43)

FUS :

Fused in sarcoma

DPRs :

Dipeptide repeat proteins

LCCS1 :

Lethal congenital contracture syndrome 1

LAAHD :

Lethal arthrogryposis with anterior horn cell disease

Ran:

Ras-related nuclear protein

References

  1. Charcot JM, Joffroy A (1869) Deux cas d’atrophie musculaire progressive avec lesions de la substance grise et des faisceaux antero-lateraux de la moelle epiniere. Arch Physiol Neurol Pathol 2:744–754

    Google Scholar 

  2. Charcot J (1874) De la sclérose latérale amyotrophique. Prog Med 2:341–453

    Google Scholar 

  3. Wijesekera LC, Leigh PN (2009) Amyotrophic lateral sclerosis. Orphanet J Rare Dis 4:3. https://doi.org/10.1186/1750-1172-4-3

    Article  PubMed  PubMed Central  Google Scholar 

  4. Swinnen B, Robberecht W (2014) The phenotypic variability of amyotrophic lateral sclerosis. Nat Rev Neurol 10(11):661–670. https://doi.org/10.1038/nrneurol.2014.184

    Article  PubMed  Google Scholar 

  5. Saberi S, Stauffer JE, Schulte DJ, Ravits J (2015) Neuropathology of amyotrophic lateral sclerosis and its variants. Neurol Clin 33(4):855–876. https://doi.org/10.1016/j.ncl.2015.07.012

    Article  PubMed  PubMed Central  Google Scholar 

  6. Gizzi M, DiRocco A, Sivak M, Cohen B (1992) Ocular motor function in motor neuron disease. Neurology 42(5):1037–1046

    Article  CAS  PubMed  Google Scholar 

  7. Nijssen J, Comley LH, Hedlund E (2017) Motor neuron vulnerability and resistance in amyotrophic lateral sclerosis. Acta Neuropathol 133(6):863–885. https://doi.org/10.1007/s00401-017-1708-8

    Article  PubMed  PubMed Central  Google Scholar 

  8. Spiller KJ, Cheung CJ, Restrepo CR, Kwong LK, Stieber AM, Trojanowski JQ, Lee VM (2016) Selective motor neuron resistance and recovery in a new inducible mouse model of TDP-43 proteinopathy. J Neurosci 36(29):7707–7717. https://doi.org/10.1523/JNEUROSCI.1457-16.2016

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  9. Cirulli ET, Lasseigne BN, Petrovski S, Sapp PC, Dion PA, Leblond CS, Couthouis J, Lu YF, Wang Q, Krueger BJ, Ren Z, Keebler J, Han Y, Levy SE, Boone BE, Wimbish JR, Waite LL, Jones AL, Carulli JP, Day-Williams AG, Staropoli JF, Xin WW, Chesi A, Raphael AR, McKenna-Yasek D, Cady J, Vianney de Jong JM, Kenna KP, Smith BN, Topp S, Miller J, Gkazi A, Consortium FS, Al-Chalabi A, van den Berg LH, Veldink J, Silani V, Ticozzi N, Shaw CE, Baloh RH, Appel S, Simpson E, Lagier-Tourenne C, Pulst SM, Gibson S, Trojanowski JQ, Elman L, McCluskey L, Grossman M, Shneider NA, Chung WK, Ravits JM, Glass JD, Sims KB, Van Deerlin VM, Maniatis T, Hayes SD, Ordureau A, Swarup S, Landers J, Baas F, Allen AS, Bedlack RS, Harper JW, Gitler AD, Rouleau GA, Brown R, Harms MB, Cooper GM, Harris T, Myers RM, Goldstein DB (2015) Exome sequencing in amyotrophic lateral sclerosis identifies risk genes and pathways. Science 347(6229):1436–1441. https://doi.org/10.1126/science.aaa3650

  10. Robberecht W, Philips T (2013) The changing scene of amyotrophic lateral sclerosis. Nat Rev Neurosci 14(4):248–264. https://doi.org/10.1038/nrn3430

    Article  CAS  PubMed  Google Scholar 

  11. Li HF, Wu ZY (2016) Genotype-phenotype correlations of amyotrophic lateral sclerosis. Transl Neurodegener 5:3. https://doi.org/10.1186/s40035-016-0050-8

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  12. Andersen PM, Al-Chalabi A (2011) Clinical genetics of amyotrophic lateral sclerosis: what do we really know? Nat Rev Neurol 7(11):603–615. https://doi.org/10.1038/nrneurol.2011.150

    Article  CAS  PubMed  Google Scholar 

  13. Reid E, Kloos M, Ashley-Koch A, Hughes L, Bevan S, Svenson IK, Graham FL, Gaskell PC, Dearlove A, Pericak-Vance MA, Rubinsztein DC, Marchuk DA (2002) A kinesin heavy chain (KIF5A) mutation in hereditary spastic paraplegia (SPG10). Am J Hum Genet 71(5):1189–1194. https://doi.org/10.1086/344210

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  14. Liu YT, Laura M, Hersheson J, Horga A, Jaunmuktane Z, Brandner S, Pittman A, Hughes D, Polke JM, Sweeney MG, Proukakis C, Janssen JC, Auer-Grumbach M, Zuchner S, Shields KG, Reilly MM, Houlden H (2014) Extended phenotypic spectrum of KIF5A mutations: from spastic paraplegia to axonal neuropathy. Neurology 83(7):612–619. https://doi.org/10.1212/WNL.0000000000000691

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  15. Morais S, Raymond L, Mairey M, Coutinho P, Brandao E, Ribeiro P, Loureiro JL, Sequeiros J, Brice A, Alonso I, Stevanin G (2017) Massive sequencing of 70 genes reveals a myriad of missing genes or mechanisms to be uncovered in hereditary spastic paraplegias. Eur J Hum Genet 25(11):1217–1228. https://doi.org/10.1038/ejhg.2017.124

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  16. Duis J, Dean S, Applegate C, Harper A, Xiao R, He W, Dollar JD, Sun LR, Waberski MB, Crawford TO, Hamosh A, Stafstrom CE (2016) KIF5A mutations cause an infantile onset phenotype including severe myoclonus with evidence of mitochondrial dysfunction. Ann Neurol 80(4):633–637. https://doi.org/10.1002/ana.24744

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  17. Rydzanicz M, Jagla M, Kosinska J, Tomasik T, Sobczak A, Pollak A, Herman-Sucharska I, Walczak A, Kwinta P, Ploski R (2017) KIF5A de novo mutation associated with myoclonic seizures and neonatal onset progressive leukoencephalopathy. Clin Genet 91(5):769–773. https://doi.org/10.1111/cge.12831

    Article  CAS  PubMed  Google Scholar 

  18. Brenner D, Yilmaz R, Muller K, Grehl T, Petri S, Meyer T, Grosskreutz J, Weydt P, Ruf W, Neuwirth C, Weber M, Pinto S, Claeys KG, Schrank B, Jordan B, Knehr A, Gunther K, Hubers A, Zeller D, Kubisch C, Jablonka S, Sendtner M, Klopstock T, de Carvalho M, Sperfeld A, Borck G, Volk AE, Dorst J, Weis J, Otto M, Schuster J, Del Tredici K, Braak H, Danzer KM, Freischmidt A, Meitinger T, Strom TM, Ludolph AC, Andersen PM, Weishaupt JH, German ALSnMNDNET (2018) Hot-spot KIF5A mutations cause familial ALS. Brain 141(3):688–697. https://doi.org/10.1093/brain/awx370

    Article  PubMed  PubMed Central  Google Scholar 

  19. Nicolas A, Kenna KP, Renton AE, Ticozzi N, Faghri F, Chia R, Dominov JA, Kenna BJ, Nalls MA, Keagle P, Rivera AM, van Rheenen W, Murphy NA, van Vugt J, Geiger JT, Van der Spek RA, Pliner HA, Shankaracharya, Smith BN, Marangi G, Topp SD, Abramzon Y, Gkazi AS, Eicher JD, Kenna A, Consortium I, Mora G, Calvo A, Mazzini L, Riva N, Mandrioli J, Caponnetto C, Battistini S, Volanti P, La Bella V, Conforti FL, Borghero G, Messina S, Simone IL, Trojsi F, Salvi F, Logullo FO, D’Alfonso S, Corrado L, Capasso M, Ferrucci L, Genomic Translation for ALSCC, Moreno CAM, Kamalakaran S, Goldstein DB, Consortium ALSS, Gitler AD, Harris T, Myers RM, Consortium NA, Phatnani H, Musunuri RL, Evani US, Abhyankar A, Zody MC, Answer ALSF, Kaye J, Finkbeiner S, Wyman SK, LeNail A, Lima L, Fraenkel E, Svendsen CN, Thompson LM, Van Eyk JE, Berry JD, Miller TM, Kolb SJ, Cudkowicz M, Baxi E, Clinical Research in ALS, Related Disorders for Therapeutic Development C, Benatar M, Taylor JP, Rampersaud E, Wu G, Wuu J, Consortium S, Lauria G, Verde F, Fogh I, Tiloca C, Comi GP, Soraru G, Cereda C, French ALSC, Corcia P, Laaksovirta H, Myllykangas L, Jansson L, Valori M, Ealing J, Hamdalla H, Rollinson S, Pickering-Brown S, Orrell RW, Sidle KC, Malaspina A, Hardy J, Singleton AB, Johnson JO, Arepalli S, Sapp PC, McKenna-Yasek D, Polak M, Asress S, Al-Sarraj S, King A, Troakes C, Vance C, de Belleroche J, Baas F, Ten Asbroek A, Munoz-Blanco JL, Hernandez DG, Ding J, Gibbs JR, Scholz SW, Floeter MK, Campbell RH, Landi F, Bowser R, Pulst SM, Ravits JM, MacGowan DJL, Kirby J, Pioro EP, Pamphlett R, Broach J, Gerhard G, Dunckley TL, Brady CB, Kowall NW, Troncoso JC, Le Ber I, Mouzat K, Lumbroso S, Heiman-Patterson TD, Kamel F, Van Den Bosch L, Baloh RH, Strom TM, Meitinger T, Shatunov A, Van Eijk KR, de Carvalho M, Kooyman M, Middelkoop B, Moisse M, McLaughlin RL, Van Es MA, Weber M, Boylan KB, Van Blitterswijk M, Rademakers R, Morrison KE, Basak AN, Mora JS, Drory VE, Shaw PJ, Turner MR, Talbot K, Hardiman O, Williams KL, Fifita JA, Nicholson GA, Blair IP, Rouleau GA, Esteban-Perez J, Garcia-Redondo A, Al-Chalabi A, Project Min EALSSC, Rogaeva E, Zinman L, Ostrow LW, Maragakis NJ, Rothstein JD, Simmons Z, Cooper-Knock J, Brice A, Goutman SA, Feldman EL, Gibson SB, Taroni F, Ratti A, Gellera C, Van Damme P, Robberecht W, Fratta P, Sabatelli M, Lunetta C, Ludolph AC, Andersen PM, Weishaupt JH, Camu W, Trojanowski JQ, Van Deerlin VM, Brown RH, Jr., van den Berg LH, Veldink JH, Harms MB, Glass JD, Stone DJ, Tienari P, Silani V, Chio A, Shaw CE, Traynor BJ, Landers JE (2018) Genome-wide analyses identify KIF5A as a novel ALS gene. Neuron 97(6):1268 e1266–1283 e1266. https://doi.org/10.1016/j.neuron.2018.02.027

  20. Rizzo F, Riboldi G, Salani S, Nizzardo M, Simone C, Corti S, Hedlund E (2014) Cellular therapy to target neuroinflammation in amyotrophic lateral sclerosis. Cell Mol Life Sci 71(6):999–1015. https://doi.org/10.1007/s00018-013-1480-4

    Article  CAS  PubMed  Google Scholar 

  21. Clement AM, Nguyen MD, Roberts EA, Garcia ML, Boillee S, Rule M, McMahon AP, Doucette W, Siwek D, Ferrante RJ, Brown RH Jr, Julien JP, Goldstein LS, Cleveland DW (2003) Wild-type nonneuronal cells extend survival of SOD1 mutant motor neurons in ALS mice. Science 302(5642):113–117. https://doi.org/10.1126/science.1086071

    Article  CAS  PubMed  Google Scholar 

  22. Boillee S, Yamanaka K, Lobsiger CS, Copeland NG, Jenkins NA, Kassiotis G, Kollias G, Cleveland DW (2006) Onset and progression in inherited ALS determined by motor neurons and microglia. Science 312(5778):1389–1392. https://doi.org/10.1126/science.1123511

    Article  CAS  PubMed  Google Scholar 

  23. Nagai M, Re DB, Nagata T, Chalazonitis A, Jessell TM, Wichterle H, Przedborski S (2007) Astrocytes expressing ALS-linked mutated SOD1 release factors selectively toxic to motor neurons. Nat Neurosci 10(5):615–622. https://doi.org/10.1038/nn1876

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  24. Brettschneider J, Toledo JB, Van Deerlin VM, Elman L, McCluskey L, Lee VM, Trojanowski JQ (2012) Microglial activation correlates with disease progression and upper motor neuron clinical symptoms in amyotrophic lateral sclerosis. PLoS One 7(6):e39216. https://doi.org/10.1371/journal.pone.0039216

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  25. O’Rourke JG, Bogdanik L, Yanez A, Lall D, Wolf AJ, Muhammad AK, Ho R, Carmona S, Vit JP, Zarrow J, Kim KJ, Bell S, Harms MB, Miller TM, Dangler CA, Underhill DM, Goodridge HS, Lutz CM, Baloh RH (2016) C9orf72 is required for proper macrophage and microglial function in mice. Science 351(6279):1324–1329. https://doi.org/10.1126/science.aaf1064

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  26. Pun S, Santos AF, Saxena S, Xu L, Caroni P (2006) Selective vulnerability and pruning of phasic motoneuron axons in motoneuron disease alleviated by CNTF. Nat Neurosci 9(3):408–419. https://doi.org/10.1038/nn1653

    Article  CAS  PubMed  Google Scholar 

  27. Hegedus J, Putman CT, Tyreman N, Gordon T (2008) Preferential motor unit loss in the SOD1 G93A transgenic mouse model of amyotrophic lateral sclerosis. J Physiol 586(14):3337–3351. https://doi.org/10.1113/jphysiol.2007.149286

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  28. Carrell RW, Lomas DA (1997) Conformational disease. Lancet 350(9071):134–138. https://doi.org/10.1016/S0140-6736(97)02073-4

    Article  CAS  PubMed  Google Scholar 

  29. Arrasate M, Mitra S, Schweitzer ES, Segal MR, Finkbeiner S (2004) Inclusion body formation reduces levels of mutant huntingtin and the risk of neuronal death. Nature 431(7010):805–810. https://doi.org/10.1038/nature02998

    Article  CAS  PubMed  Google Scholar 

  30. Ross CA, Poirier MA (2005) Opinion: what is the role of protein aggregation in neurodegeneration? Nat Rev Mol Cell Biol 6(11):891–898. https://doi.org/10.1038/nrm1742

    Article  CAS  PubMed  Google Scholar 

  31. Douglas PM, Dillin A (2010) Protein homeostasis and aging in neurodegeneration. J Cell Biol 190(5):719–729. https://doi.org/10.1083/jcb.201005144

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  32. Guo W, Chen Y, Zhou X, Kar A, Ray P, Chen X, Rao EJ, Yang M, Ye H, Zhu L, Liu J, Xu M, Yang Y, Wang C, Zhang D, Bigio EH, Mesulam M, Shen Y, Xu Q, Fushimi K, Wu JY (2011) An ALS-associated mutation affecting TDP-43 enhances protein aggregation, fibril formation and neurotoxicity. Nat Struct Mol Biol 18(7):822–830. https://doi.org/10.1038/nsmb.2053

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  33. Peters OM, Cabrera GT, Tran H, Gendron TF, McKeon JE, Metterville J, Weiss A, Wightman N, Salameh J, Kim J, Sun H, Boylan KB, Dickson D, Kennedy Z, Lin Z, Zhang YJ, Daughrity L, Jung C, Gao FB, Sapp PC, Horvitz HR, Bosco DA, Brown SP, de Jong P, Petrucelli L, Mueller C, Brown RH Jr (2015) Human C9ORF72 hexanucleotide expansion reproduces RNA foci and dipeptide repeat proteins but not neurodegeneration in BAC transgenic mice. Neuron 88(5):902–909. https://doi.org/10.1016/j.neuron.2015.11.018

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  34. O’Rourke JG, Bogdanik L, Muhammad AK, Gendron TF, Kim KJ, Austin A, Cady J, Liu EY, Zarrow J, Grant S, Ho R, Bell S, Carmona S, Simpkinson M, Lall D, Wu K, Daughrity L, Dickson DW, Harms MB, Petrucelli L, Lee EB, Lutz CM, Baloh RH (2015) C9orf72 BAC transgenic mice display typical pathologic features of ALS/FTD. Neuron 88(5):892–901. https://doi.org/10.1016/j.neuron.2015.10.027

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  35. Koppers M, Blokhuis AM, Westeneng HJ, Terpstra ML, Zundel CA, Vieira de Sa R, Schellevis RD, Waite AJ, Blake DJ, Veldink JH, van den Berg LH, Pasterkamp RJ (2015) C9orf72 ablation in mice does not cause motor neuron degeneration or motor deficits. Ann Neurol 78(3):426–438. https://doi.org/10.1002/ana.24453

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  36. Chew J, Gendron TF, Prudencio M, Sasaguri H, Zhang YJ, Castanedes-Casey M, Lee CW, Jansen-West K, Kurti A, Murray ME, Bieniek KF, Bauer PO, Whitelaw EC, Rousseau L, Stankowski JN, Stetler C, Daughrity LM, Perkerson EA, Desaro P, Johnston A, Overstreet K, Edbauer D, Rademakers R, Boylan KB, Dickson DW, Fryer JD, Petrucelli L (2015) Neurodegeneration. C9ORF72 repeat expansions in mice cause TDP-43 pathology, neuronal loss, and behavioral deficits. Science 348(6239):1151–1154. https://doi.org/10.1126/science.aaa9344

  37. Liu Y, Pattamatta A, Zu T, Reid T, Bardhi O, Borchelt DR, Yachnis AT, Ranum LP (2016) C9orf72 BAC mouse model with motor deficits and neurodegenerative features of ALS/FTD. Neuron 90(3):521–534. https://doi.org/10.1016/j.neuron.2016.04.005

    Article  CAS  PubMed  Google Scholar 

  38. Turner MR, Kiernan MC, Leigh PN, Talbot K (2009) Biomarkers in amyotrophic lateral sclerosis. Lancet Neurol 8(1):94–109. https://doi.org/10.1016/S1474-4422(08)70293-X

    Article  CAS  PubMed  Google Scholar 

  39. Turner MR, Benatar M (2015) Ensuring continued progress in biomarkers for amyotrophic lateral sclerosis. Muscle Nerve 51(1):14–18. https://doi.org/10.1002/mus.24470

    Article  PubMed  Google Scholar 

  40. Su Z, Zhang Y, Gendron TF, Bauer PO, Chew J, Yang WY, Fostvedt E, Jansen-West K, Belzil VV, Desaro P, Johnston A, Overstreet K, Oh SY, Todd PK, Berry JD, Cudkowicz ME, Boeve BF, Dickson D, Floeter MK, Traynor BJ, Morelli C, Ratti A, Silani V, Rademakers R, Brown RH, Rothstein JD, Boylan KB, Petrucelli L, Disney MD (2014) Discovery of a biomarker and lead small molecules to target r(GGGGCC)-associated defects in c9FTD/ALS. Neuron 83(5):1043–1050. https://doi.org/10.1016/j.neuron.2014.07.041

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  41. Zhang J, Ito H, Wate R, Ohnishi S, Nakano S, Kusaka H (2006) Altered distributions of nucleocytoplasmic transport-related proteins in the spinal cord of a mouse model of amyotrophic lateral sclerosis. Acta Neuropathol 112(6):673–680. https://doi.org/10.1007/s00401-006-0130-4

    Article  CAS  PubMed  Google Scholar 

  42. Kinoshita Y, Ito H, Hirano A, Fujita K, Wate R, Nakamura M, Kaneko S, Nakano S, Kusaka H (2009) Nuclear contour irregularity and abnormal transporter protein distribution in anterior horn cells in amyotrophic lateral sclerosis. J Neuropathol Exp Neurol 68(11):1184–1192. https://doi.org/10.1097/NEN.0b013e3181bc3bec

    Article  CAS  PubMed  Google Scholar 

  43. Dormann D, Rodde R, Edbauer D, Bentmann E, Fischer I, Hruscha A, Than ME, Mackenzie IR, Capell A, Schmid B, Neumann M, Haass C (2010) ALS-associated fused in sarcoma (FUS) mutations disrupt Transportin-mediated nuclear import. EMBO J 29(16):2841–2857. https://doi.org/10.1038/emboj.2010.143

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  44. Nagara Y, Tateishi T, Yamasaki R, Hayashi S, Kawamura M, Kikuchi H, Iinuma KM, Tanaka M, Iwaki T, Matsushita T, Ohyagi Y, Kira J (2013) Impaired cytoplasmic-nuclear transport of hypoxia-inducible factor-1alpha in amyotrophic lateral sclerosis. Brain Pathol 23(5):534–546. https://doi.org/10.1111/bpa.12040

    Article  PubMed  PubMed Central  Google Scholar 

  45. Ward ME, Taubes A, Chen R, Miller BL, Sephton CF, Gelfand JM, Minami S, Boscardin J, Martens LH, Seeley WW, Yu G, Herz J, Filiano AJ, Arrant AE, Roberson ED, Kraft TW, Farese RV Jr, Green A, Gan L (2014) Early retinal neurodegeneration and impaired Ran-mediated nuclear import of TDP-43 in progranulin-deficient FTLD. J Exp Med 211(10):1937–1945. https://doi.org/10.1084/jem.20140214

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  46. Xiao S, MacNair L, McGoldrick P, McKeever PM, McLean JR, Zhang M, Keith J, Zinman L, Rogaeva E, Robertson J (2015) Isoform-specific antibodies reveal distinct subcellular localizations of C9orf72 in amyotrophic lateral sclerosis. Ann Neurol 78(4):568–583. https://doi.org/10.1002/ana.24469

    Article  CAS  PubMed  Google Scholar 

  47. Freibaum BD, Lu Y, Lopez-Gonzalez R, Kim NC, Almeida S, Lee KH, Badders N, Valentine M, Miller BL, Wong PC, Petrucelli L, Kim HJ, Gao FB, Taylor JP (2015) GGGGCC repeat expansion in C9orf72 compromises nucleocytoplasmic transport. Nature 525(7567):129–133. https://doi.org/10.1038/nature14974

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  48. Zhang K, Donnelly CJ, Haeusler AR, Grima JC, Machamer JB, Steinwald P, Daley EL, Miller SJ, Cunningham KM, Vidensky S, Gupta S, Thomas MA, Hong I, Chiu SL, Huganir RL, Ostrow LW, Matunis MJ, Wang J, Sattler R, Lloyd TE, Rothstein JD (2015) The C9orf72 repeat expansion disrupts nucleocytoplasmic transport. Nature 525(7567):56–61. https://doi.org/10.1038/nature14973

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  49. Woerner AC, Frottin F, Hornburg D, Feng LR, Meissner F, Patra M, Tatzelt J, Mann M, Winklhofer KF, Hartl FU, Hipp MS (2016) Cytoplasmic protein aggregates interfere with nucleocytoplasmic transport of protein and RNA. Science 351(6269):173–176. https://doi.org/10.1126/science.aad2033

    Article  CAS  PubMed  Google Scholar 

  50. Shang J, Yamashita T, Nakano Y, Morihara R, Li X, Feng T, Liu X, Huang Y, Fukui Y, Hishikawa N, Ohta Y, Abe K (2017) Aberrant distributions of nuclear pore complex proteins in ALS mice and ALS patients. Neuroscience 350:158–168. https://doi.org/10.1016/j.neuroscience.2017.03.024

    Article  CAS  PubMed  Google Scholar 

  51. Zhong Y, Wang J, Henderson MJ, Yang P, Hagen BM, Siddique T, Vogel BE, Deng HX, Fang S (2017) Nuclear export of misfolded SOD1 mediated by a normally buried NES-like sequence reduces proteotoxicity in the nucleus. Elife. https://doi.org/10.7554/elife.23759

    Article  PubMed  PubMed Central  Google Scholar 

  52. Grima JC, Daigle JG, Arbez N, Cunningham KC, Zhang K, Ochaba J, Geater C, Morozko E, Stocksdale J, Glatzer JC, Pham JT, Ahmed I, Peng Q, Wadhwa H, Pletnikova O, Troncoso JC, Duan W, Snyder SH, Ranum LPW, Thompson LM, Lloyd TE, Ross CA, Rothstein JD (2017) Mutant huntingtin disrupts the nuclear pore complex. Neuron 94(1):93 e106–107 e106. https://doi.org/10.1016/j.neuron.2017.03.023

    Article  CAS  Google Scholar 

  53. Gasset-Rosa F, Chillon-Marinas C, Goginashvili A, Atwal RS, Artates JW, Tabet R, Wheeler VC, Bang AG, Cleveland DW, Lagier-Tourenne C (2017) Polyglutamine-expanded huntingtin exacerbates age-related disruption of nuclear integrity and nucleocytoplasmic transport. Neuron 94(1):48 e44–57 e44. https://doi.org/10.1016/j.neuron.2017.03.027

    Article  CAS  Google Scholar 

  54. Solomon DA, Stepto A, Au WH, Adachi Y, Diaper DC, Hall R, Rekhi A, Boudi A, Tziortzouda P, Lee YB, Smith B, Bridi JC, Spinelli G, Dearlove J, Humphrey DM, Gallo JM, Troakes C, Fanto M, Soller M, Rogelj B, Parsons RB, Shaw CE, Hortobagyi T, Hirth F (2018) A feedback loop between dipeptide-repeat protein, TDP-43 and karyopherin-alpha mediates C9orf72-related neurodegeneration. Brain 141(10):2908–2924. https://doi.org/10.1093/brain/awy241

    Article  PubMed  PubMed Central  Google Scholar 

  55. Eftekharzadeh B, Daigle JG, Kapinos LE, Coyne A, Schiantarelli J, Carlomagno Y, Cook C, Miller SJ, Dujardin S, Amaral AS, Grima JC, Bennett RE, Tepper K, DeTure M, Vanderburgh CR, Corjuc BT, DeVos SL, Gonzalez JA, Chew J, Vidensky S, Gage FH, Mertens J, Troncoso J, Mandelkow E, Salvatella X, Lim RYH, Petrucelli L, Wegmann S, Rothstein JD, Hyman BT (2018) Tau Protein Disrupts Nucleocytoplasmic Transport in Alzheimer’s Disease. Neuron 99(5):925 e927–940 e927. https://doi.org/10.1016/j.neuron.2018.07.039

    Article  CAS  Google Scholar 

  56. Rush MG, Drivas G, D’Eustachio P (1996) The small nuclear GTPase Ran: how much does it run? Bioessays 18(2):103–112

    Article  CAS  PubMed  Google Scholar 

  57. Nachury MV, Weis K (1999) The direction of transport through the nuclear pore can be inverted. Proc Natl Acad Sci USA 96(17):9622–9627

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  58. Akhtar N, Hagan H, Lopilato JE, Corbett AH (2001) Functional analysis of the yeast Ran exchange factor Prp20p: in vivo evidence for the RanGTP gradient model. Mol Genet Genom 265(5):851–864

    Article  CAS  Google Scholar 

  59. Kalab P, Weis K, Heald R (2002) Visualization of a Ran-GTP gradient in interphase and mitotic Xenopus egg extracts. Science 295(5564):2452–2456

    Article  CAS  PubMed  Google Scholar 

  60. Kalab P, Pralle A, Isacoff EY, Heald R, Weis K (2006) Analysis of a RanGTP-regulated gradient in mitotic somatic cells. Nature 440(7084):697–701. https://doi.org/10.1038/nature04589

    Article  CAS  PubMed  Google Scholar 

  61. Bischoff FR, Ponstingl H (1991) Catalysis of guanine nucleotide exchange on Ran by the mitotic regulator RCC1. Nature 354(6348):80–82

    Article  CAS  PubMed  Google Scholar 

  62. Bischoff FR, Ponstingl H (1991) Mitotic regulator protein RCC1 is complexed with a nuclear ras-related polypeptide. Proc Natl Acad Sci USA 88(23):10830–10834

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  63. Klebe C, Prinz H, Wittinghofer A, Goody RS (1995) The kinetic mechanism of Ran–nucleotide exchange catalyzed by RCC1. Biochemistry (Mosc) 34(39):12543–12552

    Article  CAS  Google Scholar 

  64. Klebe C, Bischoff FR, Ponstingl H, Wittinghofer A (1995) Interaction of the nuclear GTP-binding protein Ran with its regulatory proteins RCC1 and RanGAP1. Biochemistry (Mosc) 34(2):639–647

    Article  CAS  Google Scholar 

  65. Bischoff FR, Klebe C, Kretschmer J, Wittinghofer A, Ponstingl H (1994) RanGAP1 induces GTPase activity of nuclear Ras-related Ran. Proc Natl Acad Sci USA 91(7):2587–2591

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  66. Bischoff FR, Krebber H, Kempf T, Hermes I, Ponstingl H (1995) Human RanGTPase-activating protein RanGAP1 is a homologue of yeast Rna1p involved in mRNA processing and transport. Proc Natl Acad Sci USA 92(5):1749–1753

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  67. Becker J, Melchior F, Gerke V, Bischoff FR, Ponstingl H, Wittinghofer A (1995) RNA1 encodes a GTPase-activating protein specific for Gsp1p, the Ran/TC4 homologue of Saccharomyces cerevisiae. J Biol Chem 270(20):11860–11865

    Article  CAS  PubMed  Google Scholar 

  68. Gorlich D, Pante N, Kutay U, Aebi U, Bischoff FR (1996) Identification of different roles for RanGDP and RanGTP in nuclear protein import. EMBO J 15(20):5584–5594

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  69. Izaurralde E, Kutay U, von Kobbe C, Mattaj IW, Gorlich D (1997) The asymmetric distribution of the constituents of the Ran system is essential for transport into and out of the nucleus. EMBO J 16(21):6535–6547

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  70. Gorlich D, Seewald MJ, Ribbeck K (2003) Characterization of Ran-driven cargo transport and the RanGTPase system by kinetic measurements and computer simulation. EMBO J 22(5):1088–1100. https://doi.org/10.1093/emboj/cdg113

    Article  PubMed  PubMed Central  Google Scholar 

  71. Ribbeck K, Lipowsky G, Kent HM, Stewart M, Gorlich D (1998) NTF2 mediates nuclear import of Ran. EMBO J 17(22):6587–6598

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  72. Smith A, Brownawell A, Macara IG (1998) Nuclear import of Ran is mediated by the transport factor NTF2. Curr Biol 8(25):1403–1406

    Article  CAS  PubMed  Google Scholar 

  73. Feldherr CM (1962) The nuclear annuli as pathways for nucleocytoplasmic exchanges. J Cell Biol 14:65–72

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  74. Kose S, Imamoto N, Tachibana T, Shimamoto T, Yoneda Y (1997) Ran-unassisted nuclear migration of a 97-kD component of nuclear pore-targeting complex. J Cell Biol 139(4):841–849

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  75. Schwoebel ED, Talcott B, Cushman I, Moore MS (1998) Ran-dependent signal-mediated nuclear import does not require GTP hydrolysis by Ran. J Biol Chem 273(52):35170–35175

    Article  CAS  PubMed  Google Scholar 

  76. Nakielny S, Dreyfuss G (1998) Import and export of the nuclear protein import receptor transportin by a mechanism independent of GTP hydrolysis. Curr Biol 8(2):89–95

    Article  CAS  PubMed  Google Scholar 

  77. Ribbeck K, Kutay U, Paraskeva E, Gorlich D (1999) The translocation of transportin-cargo complexes through nuclear pores is independent of both Ran and energy. Curr Biol 9(1):47–50

    Article  CAS  PubMed  Google Scholar 

  78. Paine PL, Moore LC, Horowitz SB (1975) Nuclear envelope permeability. Nature 254(5496):109–114

    Article  CAS  PubMed  Google Scholar 

  79. Paine PL (1975) Nucleocytoplasmic movement of fluorescent tracers microinjected into living salivary gland cells. J Cell Biol 66(3):652–657

    Article  CAS  PubMed  Google Scholar 

  80. Gorlich D, Kutay U (1999) Transport between the cell nucleus and the cytoplasm. Annu Rev Cell Dev Biol 15:607–660

    Article  CAS  PubMed  Google Scholar 

  81. Keminer O, Siebrasse JP, Zerf K, Peters R (1999) Optical recording of signal-mediated protein transport through single nuclear pore complexes. Proc Natl Acad Sci USA 96(21):11842–11847

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  82. Ribbeck K, Gorlich D (2001) Kinetic analysis of translocation through nuclear pore complexes. EMBO J 20(6):1320–1330

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  83. Naim B, Zbaida D, Dagan S, Kapon R, Reich Z (2009) Cargo surface hydrophobicity is sufficient to overcome the nuclear pore complex selectivity barrier. EMBO J 28(18):2697–2705. https://doi.org/10.1038/emboj.2009.225

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  84. Mohr D, Frey S, Fischer T, Guttler T, Gorlich D (2009) Characterisation of the passive permeability barrier of nuclear pore complexes. EMBO J 28(17):2541–2553. https://doi.org/10.1038/emboj.2009.200

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  85. Tu LC, Fu G, Zilman A, Musser SM (2013) Large cargo transport by nuclear pores: implications for the spatial organization of FG-nucleoporins. EMBO J 32(24):3220–3230. https://doi.org/10.1038/emboj.2013.239

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  86. Naim B, Brumfeld V, Kapon R, Kiss V, Nevo R, Reich Z (2007) Passive and facilitated transport in nuclear pore complexes is largely uncoupled. J Biol Chem 282(6):3881–3888. https://doi.org/10.1074/jbc.M608329200

    Article  CAS  PubMed  Google Scholar 

  87. Fiserova J, Richards SA, Wente SR, Goldberg MW (2010) Facilitated transport and diffusion take distinct spatial routes through the nuclear pore complex. J Cell Sci 123(Pt 16):2773–2780. https://doi.org/10.1242/jcs.070730

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  88. Cardarelli F, Tosti L, Serresi M, Beltram F, Bizzarri R (2012) Fluorescent recovery after photobleaching (FRAP) analysis of nuclear export rates identifies intrinsic features of nucleocytoplasmic transport. J Biol Chem 287(8):5554–5561. https://doi.org/10.1074/jbc.M111.304899

    Article  CAS  PubMed  Google Scholar 

  89. Kimura M, Imamoto N (2014) Biological significance of the importin-beta family-dependent nucleocytoplasmic transport pathways. Traffic 15(7):727–748. https://doi.org/10.1111/tra.12174

    Article  CAS  PubMed  Google Scholar 

  90. Kimura M, Morinaka Y, Imai K, Kose S, Horton P, Imamoto N (2017) Extensive cargo identification reveals distinct biological roles of the 12 importin pathways. Elife. https://doi.org/10.7554/elife.21184

    Article  PubMed  PubMed Central  Google Scholar 

  91. Aksu M, Pleiner T, Karaca S, Kappert C, Dehne HJ, Seibel K, Urlaub H, Bohnsack MT, Gorlich D (2018) Xpo7 is a broad-spectrum exportin and a nuclear import receptor. J Cell Biol 217(7):2329–2340. https://doi.org/10.1083/jcb.201712013

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  92. Kirli K, Karaca S, Dehne HJ, Samwer M, Pan KT, Lenz C, Urlaub H, Gorlich D (2015) A deep proteomics perspective on CRM1-mediated nuclear export and nucleocytoplasmic partitioning. Elife. https://doi.org/10.7554/elife.11466

    Article  PubMed  PubMed Central  Google Scholar 

  93. Kutay U, Bischoff FR, Kostka S, Kraft R, Gorlich D (1997) Export of importin alpha from the nucleus is mediated by a specific nuclear transport factor. Cell 90(6):1061–1071

    Article  CAS  PubMed  Google Scholar 

  94. Fornerod M, van Deursen J, van Baal S, Reynolds A, Davis D, Murti KG, Fransen J, Grosveld G (1997) The human homologue of yeast CRM1 is in a dynamic subcomplex with CAN/Nup214 and a novel nuclear pore component Nup88. EMBO J 16(4):807–816

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  95. Gorlich D, Dabrowski M, Bischoff FR, Kutay U, Bork P, Hartmann E, Prehn S, Izaurralde E (1997) A novel class of RanGTP binding proteins. J Cell Biol 138(1):65–80

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  96. Vetter IR, Arndt A, Kutay U, Gorlich D, Wittinghofer A (1999) Structural view of the Ran–Importin beta interaction at 2.3 A resolution. Cell 97(5):635–646

  97. Villa Braslavsky CI, Nowak C, Gorlich D, Wittinghofer A, Kuhlmann J (2000) Different structural and kinetic requirements for the interaction of Ran with the Ran-binding domains from RanBP2 and importin-beta. Biochemistry (Mosc) 39(38):11629–11639

    Article  CAS  Google Scholar 

  98. Kutay U, Hartmann E, Treichel N, Calado A, Carmo-Fonseca M, Prehn S, Kraft R, Gorlich D, Bischoff FR (2000) Identification of two novel RanGTP-binding proteins belonging to the importin beta superfamily. J Biol Chem 275(51):40163–40168. https://doi.org/10.1074/jbc.M006242200

    Article  CAS  PubMed  Google Scholar 

  99. Mingot JM, Bohnsack MT, Jakle U, Gorlich D (2004) Exportin 7 defines a novel general nuclear export pathway. EMBO J 23(16):3227–3236. https://doi.org/10.1038/sj.emboj.7600338

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  100. Radu A, Blobel G, Moore MS (1995) Identification of a protein complex that is required for nuclear protein import and mediates docking of import substrate to distinct nucleoporins. Proc Natl Acad Sci USA 92(5):1769–1773

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  101. Bischoff FR, Gorlich D (1997) RanBP1 is crucial for the release of RanGTP from importin beta-related nuclear transport factors. FEBS Lett 419(2–3):249–254

    Article  CAS  PubMed  Google Scholar 

  102. Deane R, Schafer W, Zimmermann HP, Mueller L, Gorlich D, Prehn S, Ponstingl H, Bischoff FR (1997) Ran-binding protein 5 (RanBP5) is related to the nuclear transport factor importin-beta but interacts differently with RanBP1. Mol Cell Biol 17(9):5087–5096

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  103. Stade K, Ford CS, Guthrie C, Weis K (1997) Exportin 1 (Crm1p) is an essential nuclear export factor. Cell 90(6):1041–1050

    Article  CAS  PubMed  Google Scholar 

  104. Fornerod M, Ohno M, Yoshida M, Mattaj IW (1997) CRM1 is an export receptor for leucine-rich nuclear export signals. Cell 90(6):1051–1060

    Article  CAS  PubMed  Google Scholar 

  105. Kutay U, Lipowsky G, Izaurralde E, Bischoff FR, Schwarzmaier P, Hartmann E, Gorlich D (1998) Identification of a tRNA-specific nuclear export receptor. Mol Cell 1(3):359–369

    Article  CAS  PubMed  Google Scholar 

  106. Paraskeva E, Izaurralde E, Bischoff FR, Huber J, Kutay U, Hartmann E, Luhrmann R, Gorlich D (1999) CRM1-mediated recycling of snurportin 1 to the cytoplasm. J Cell Biol 145(2):255–264

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  107. Askjaer P, Bachi A, Wilm M, Bischoff FR, Weeks DL, Ogniewski V, Ohno M, Niehrs C, Kjems J, Mattaj IW, Fornerod M (1999) RanGTP-regulated interactions of CRM1 with nucleoporins and a shuttling DEAD-box helicase. Mol Cell Biol 19(9):6276–6285

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  108. Dong X, Biswas A, Chook YM (2009) Structural basis for assembly and disassembly of the CRM1 nuclear export complex. Nat Struct Mol Biol 16(5):558–560. https://doi.org/10.1038/nsmb.1586

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  109. Fukuda M, Asano S, Nakamura T, Adachi M, Yoshida M, Yanagida M, Nishida E (1997) CRM1 is responsible for intracellular transport mediated by the nuclear export signal. Nature 390(6657):308–311

    Article  CAS  PubMed  Google Scholar 

  110. Ossareh-Nazari B, Bachelerie F, Dargemont C (1997) Evidence for a role of CRM1 in signal-mediated nuclear protein export. Science 278(5335):141–144

    Article  CAS  PubMed  Google Scholar 

  111. Dong X, Biswas A, Suel KE, Jackson LK, Martinez R, Gu H, Chook YM (2009) Structural basis for leucine-rich nuclear export signal recognition by CRM1. Nature 458(7242):1136–1141. https://doi.org/10.1038/nature07975

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  112. Guttler T, Madl T, Neumann P, Deichsel D, Corsini L, Monecke T, Ficner R, Sattler M, Gorlich D (2010) NES consensus redefined by structures of PKI-type and Rev-type nuclear export signals bound to CRM1. Nat Struct Mol Biol 17(11):1367–1376. https://doi.org/10.1038/nsmb.1931

    Article  CAS  PubMed  Google Scholar 

  113. Jakel S, Gorlich D (1998) Importin beta, transportin, RanBP5 and RanBP7 mediate nuclear import of ribosomal proteins in mammalian cells. EMBO J 17(15):4491–4502

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  114. Truant R, Cullen BR (1999) The arginine-rich domains present in human immunodeficiency virus type 1 Tat and Rev function as direct importin beta-dependent nuclear localization signals. Mol Cell Biol 19(2):1210–1217

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  115. Adam EJ, Adam SA (1994) Identification of cytosolic factors required for nuclear location sequence-mediated binding to the nuclear envelope. J Cell Biol 125(3):547–555

    Article  CAS  PubMed  Google Scholar 

  116. Gorlich D, Prehn S, Laskey RA, Hartmann E (1994) Isolation of a protein that is essential for the first step of nuclear protein import. Cell 79(5):767–778

    Article  CAS  PubMed  Google Scholar 

  117. Gorlich D, Kostka S, Kraft R, Dingwall C, Laskey RA, Hartmann E, Prehn S (1995) Two different subunits of importin cooperate to recognize nuclear localization signals and bind them to the nuclear envelope. Curr Biol 5(4):383–392

    Article  CAS  PubMed  Google Scholar 

  118. Lange A, Mills RE, Lange CJ, Stewart M, Devine SE, Corbett AH (2007) Classical nuclear localization signals: definition, function, and interaction with importin alpha. J Biol Chem 282(8):5101–5105. https://doi.org/10.1074/jbc.R600026200

    Article  CAS  PubMed  Google Scholar 

  119. Jakel S, Albig W, Kutay U, Bischoff FR, Schwamborn K, Doenecke D, Gorlich D (1999) The importin beta/importin 7 heterodimer is a functional nuclear import receptor for histone H1. EMBO J 18(9):2411–2423

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  120. Lee BJ, Cansizoglu AE, Suel KE, Louis TH, Zhang Z, Chook YM (2006) Rules for nuclear localization sequence recognition by karyopherin beta 2. Cell 126(3):543–558. https://doi.org/10.1016/j.cell.2006.05.049

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  121. Suel KE, Gu H, Chook YM (2008) Modular organization and combinatorial energetics of proline-tyrosine nuclear localization signals. PLoS Biol 6(6):e137. https://doi.org/10.1371/journal.pbio.0060137

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  122. Wang P, Liu GH, Wu K, Qu J, Huang B, Zhang X, Zhou X, Gerace L, Chen C (2009) Repression of classical nuclear export by S-nitrosylation of CRM1. J Cell Sci 122(Pt 20):3772–3779. https://doi.org/10.1242/jcs.057026

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  123. Riviere Y, Blank V, Kourilsky P, Israel A (1991) Processing of the precursor of NF-kappa B by the HIV-1 protease during acute infection. Nature 350(6319):625–626. https://doi.org/10.1038/350625a0

    Article  CAS  PubMed  Google Scholar 

  124. Li S, Ku CY, Farmer AA, Cong YS, Chen CF, Lee WH (1998) Identification of a novel cytoplasmic protein that specifically binds to nuclear localization signal motifs. J Biol Chem 273(11):6183–6189

    Article  CAS  PubMed  Google Scholar 

  125. Craig E, Zhang ZK, Davies KP, Kalpana GV (2002) A masked NES in INI1/hSNF5 mediates hCRM1-dependent nuclear export: implications for tumorigenesis. EMBO J 21(1–2):31–42. https://doi.org/10.1093/emboj/21.1.31

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  126. Saporita AJ, Zhang Q, Navai N, Dincer Z, Hahn J, Cai X, Wang Z (2003) Identification and characterization of a ligand-regulated nuclear export signal in androgen receptor. J Biol Chem 278(43):41998–42005. https://doi.org/10.1074/jbc.M302460200

    Article  CAS  PubMed  Google Scholar 

  127. Fischer U, Schauble N, Schutz S, Altvater M, Chang Y, Faza MB, Panse VG (2015) A non-canonical mechanism for Crm1-export cargo complex assembly. Elife. https://doi.org/10.7554/elife.05745

    Article  PubMed  PubMed Central  Google Scholar 

  128. Cardarelli F, Bizzarri R, Serresi M, Albertazzi L, Beltram F (2009) Probing nuclear localization signal-importin alpha binding equilibria in living cells. J Biol Chem 284(52):36638–36646. https://doi.org/10.1074/jbc.M109.036699

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  129. Kubitscheck U, Grunwald D, Hoekstra A, Rohleder D, Kues T, Siebrasse JP, Peters R (2005) Nuclear transport of single molecules: dwell times at the nuclear pore complex. J Cell Biol 168(2):233–243. https://doi.org/10.1083/jcb.200411005

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  130. Mor A, Suliman S, Ben-Yishay R, Yunger S, Brody Y, Shav-Tal Y (2010) Dynamics of single mRNP nucleocytoplasmic transport and export through the nuclear pore in living cells. Nat Cell Biol 12(6):543–552. https://doi.org/10.1038/ncb2056

    Article  CAS  PubMed  Google Scholar 

  131. Lim RY, Fahrenkrog B, Koser J, Schwarz-Herion K, Deng J, Aebi U (2007) Nanomechanical basis of selective gating by the nuclear pore complex. Science 318(5850):640–643. https://doi.org/10.1126/science.1145980

    Article  CAS  PubMed  Google Scholar 

  132. Cardarelli F, Lanzano L, Gratton E (2012) Capturing directed molecular motion in the nuclear pore complex of live cells. Proc Natl Acad Sci USA 109(25):9863–9868. https://doi.org/10.1073/pnas.1200486109

    Article  PubMed  PubMed Central  Google Scholar 

  133. Koyama M, Matsuura Y (2010) An allosteric mechanism to displace nuclear export cargo from CRM1 and RanGTP by RanBP1. EMBO J 29(12):2002–2013. https://doi.org/10.1038/emboj.2010.89

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  134. Vetter IR, Nowak C, Nishimoto T, Kuhlmann J, Wittinghofer A (1999) Structure of a Ran-binding domain complexed with Ran bound to a GTP analogue: implications for nuclear transport. Nature 398(6722):39–46

    Article  CAS  PubMed  Google Scholar 

  135. Coutavas E, Ren M, Oppenheim JD, D’Eustachio P, Rush MG (1993) Characterization of proteins that interact with the cell-cycle regulatory protein Ran/TC4. Nature 366(6455):585–587

    Article  CAS  PubMed  Google Scholar 

  136. Lounsbury KM, Beddow AL, Macara IG (1994) A family of proteins that stabilize the Ran/TC4 GTPase in its GTP-bound conformation. J Biol Chem 269(15):11285–11290

    CAS  PubMed  Google Scholar 

  137. Beddow AL, Richards SA, Orem NR, Macara IG (1995) The Ran/TC4 GTPase-binding domain: identification by expression cloning and characterization of a conserved sequence motif. Proc Natl Acad Sci USA 92(8):3328–3332

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  138. Ferreira PA, Hom JT, Pak WL (1995) Retina-specifically expressed novel subtypes of bovine cyclophilin. J Biol Chem 270(39):23179–23188

    Article  CAS  PubMed  Google Scholar 

  139. Wilken N, Senecal JL, Scheer U, Dabauvalle MC (1995) Localization of the Ran-GTP binding protein RanBP2 at the cytoplasmic side of the nuclear pore complex. Eur J Cell Biol 68(3):211–219

    CAS  PubMed  Google Scholar 

  140. Wu J, Matunis MJ, Kraemer D, Blobel G, Coutavas E (1995) Nup358, a cytoplasmically exposed nucleoporin with peptide repeats, Ran-GTP binding sites, zinc fingers, a cyclophilin A homologous domain, and a leucine-rich region. J Biol Chem 270(23):14209–14213

    Article  CAS  PubMed  Google Scholar 

  141. Yokoyama N, Hayashi N, Seki T, Pante N, Ohba T, Nishii K, Kuma K, Hayashida T, Miyata T, Aebi U et al (1995) A giant nucleopore protein that binds Ran/TC4. Nature 376(6536):184–188

    Article  CAS  PubMed  Google Scholar 

  142. Delphin C, Guan T, Melchior F, Gerace L (1997) RanGTP targets p97 to RanBP2, a filamentous protein localized at the cytoplasmic periphery of the nuclear pore complex. Mol Biol Cell 8(12):2379–2390

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  143. Forler D, Rabut G, Ciccarelli FD, Herold A, Kocher T, Niggeweg R, Bork P, Ellenberg J, Izaurralde E (2004) RanBP2/Nup358 provides a major binding site for NXF1-p15 dimers at the nuclear pore complex and functions in nuclear mRNA export. Mol Cell Biol 24(3):1155–1167

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  144. Ciccarelli FD, von Mering C, Suyama M, Harrington ED, Izaurralde E, Bork P (2005) Complex genomic rearrangements lead to novel primate gene function. Genome Res 15(3):343–351. https://doi.org/10.1101/gr.3266405

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  145. Singh BB, Patel HH, Roepman R, Schick D, Ferreira PA (1999) The zinc finger cluster domain of RanBP2 is a specific docking site for the nuclear export factor, exportin-1. J Biol Chem 274(52):37370–37378

    Article  CAS  PubMed  Google Scholar 

  146. Bischoff FR, Krebber H, Smirnova E, Dong W, Ponstingl H (1995) Co-activation of RanGTPase and inhibition of GTP dissociation by Ran-GTP binding protein RanBP1. EMBO J 14(4):705–715

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  147. Seewald MJ, Korner C, Wittinghofer A, Vetter IR (2002) RanGAP mediates GTP hydrolysis without an arginine finger. Nature 415(6872):662–666

    Article  CAS  PubMed  Google Scholar 

  148. Mahajan R, Delphin C, Guan T, Gerace L, Melchior F (1997) A small ubiquitin-related polypeptide involved in targeting RanGAP1 to nuclear pore complex protein RanBP2. Cell 88(1):97–107

    Article  CAS  PubMed  Google Scholar 

  149. Saitoh H, Pu R, Cavenagh M, Dasso M (1997) RanBP2 associates with Ubc9p and a modified form of RanGAP1. Proc Natl Acad Sci USA 94(8):3736–3741

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  150. Lee GW, Melchior F, Matunis MJ, Mahajan R, Tian Q, Anderson P (1998) Modification of Ran GTPase-activating protein by the small ubiquitin-related modifier SUMO-1 requires Ubc9, an E2-type ubiquitin-conjugating enzyme homologue. J Biol Chem 273(11):6503–6507

    Article  CAS  PubMed  Google Scholar 

  151. Saitoh H, Sparrow DB, Shiomi T, Pu RT, Nishimoto T, Mohun TJ, Dasso M (1998) Ubc9p and the conjugation of SUMO-1 to RanGAP1 and RanBP2. Curr Biol 8(2):121–124

    Article  CAS  PubMed  Google Scholar 

  152. Mueller L, Cordes VC, Bischoff FR, Ponstingl H (1998) Human RanBP3, a group of nuclear RanGTP binding proteins. FEBS Lett 427(3):330–336

    Article  CAS  PubMed  Google Scholar 

  153. Englmeier L, Fornerod M, Bischoff FR, Petosa C, Mattaj IW, Kutay U (2001) RanBP3 influences interactions between CRM1 and its nuclear protein export substrates. EMBO Rep 2(10):926–932. https://doi.org/10.1093/embo-reports/kve200

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  154. Lindsay ME, Holaska JM, Welch K, Paschal BM, Macara IG (2001) Ran-binding protein 3 is a cofactor for Crm1-mediated nuclear protein export. J Cell Biol 153(7):1391–1402

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  155. Langer K, Dian C, Rybin V, Muller CW, Petosa C (2011) Insights into the function of the CRM1 cofactor RanBP3 from the structure of its Ran-binding domain. PLoS One 6(2):e17011. https://doi.org/10.1371/journal.pone.0017011

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  156. Arts GJ, Fornerod M, Mattaj IW (1998) Identification of a nuclear export receptor for tRNA. Curr Biol 8(6):305–314

    Article  CAS  PubMed  Google Scholar 

  157. Brownawell AM, Macara IG (2002) Exportin-5, a novel karyopherin, mediates nuclear export of double-stranded RNA binding proteins. J Cell Biol 156(1):53–64. https://doi.org/10.1083/jcb.200110082

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  158. Clouse KN, Luo MJ, Zhou Z, Reed R (2001) A Ran-independent pathway for export of spliced mRNA. Nat Cell Biol 3(1):97–99. https://doi.org/10.1038/35050625

    Article  CAS  PubMed  Google Scholar 

  159. Segref A, Sharma K, Doye V, Hellwig A, Huber J, Luhrmann R, Hurt E (1997) Mex67p, a novel factor for nuclear mRNA export, binds to both poly(A)+ RNA and nuclear pores. EMBO J 16(11):3256–3271. https://doi.org/10.1093/emboj/16.11.3256

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  160. Ossareh-Nazari B, Maison C, Black BE, Levesque L, Paschal BM, Dargemont C (2000) RanGTP-binding protein NXT1 facilitates nuclear export of different classes of RNA in vitro. Mol Cell Biol 20(13):4562–4571

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  161. Herold A, Klymenko T, Izaurralde E (2001) NXF1/p15 heterodimers are essential for mRNA nuclear export in Drosophila. RNA 7(12):1768–1780

    CAS  PubMed  PubMed Central  Google Scholar 

  162. Strasser K, Masuda S, Mason P, Pfannstiel J, Oppizzi M, Rodriguez-Navarro S, Rondon AG, Aguilera A, Struhl K, Reed R, Hurt E (2002) TREX is a conserved complex coupling transcription with messenger RNA export. Nature 417(6886):304–308. https://doi.org/10.1038/nature746

    Article  CAS  PubMed  Google Scholar 

  163. Masuda S, Das R, Cheng H, Hurt E, Dorman N, Reed R (2005) Recruitment of the human TREX complex to mRNA during splicing. Genes Dev 19(13):1512–1517. https://doi.org/10.1101/gad.1302205

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  164. Hautbergue GM, Hung ML, Golovanov AP, Lian LY, Wilson SA (2008) Mutually exclusive interactions drive handover of mRNA from export adaptors to TAP. Proc Natl Acad Sci USA 105(13):5154–5159. https://doi.org/10.1073/pnas.0709167105

    Article  PubMed  PubMed Central  Google Scholar 

  165. Hautbergue GM, Hung ML, Walsh MJ, Snijders AP, Chang CT, Jones R, Ponting CP, Dickman MJ, Wilson SA (2009) UIF, a New mRNA export adaptor that works together with REF/ALY, requires FACT for recruitment to mRNA. Curr Biol 19(22):1918–1924. https://doi.org/10.1016/j.cub.2009.09.041

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  166. Viphakone N, Hautbergue GM, Walsh M, Chang CT, Holland A, Folco EG, Reed R, Wilson SA (2012) TREX exposes the RNA-binding domain of Nxf1 to enable mRNA export. Nat Commun 3:1006. https://doi.org/10.1038/ncomms2005

    Article  CAS  PubMed  Google Scholar 

  167. Chi B, Wang Q, Wu G, Tan M, Wang L, Shi M, Chang X, Cheng H (2013) Aly and THO are required for assembly of the human TREX complex and association of TREX components with the spliced mRNA. Nucleic Acids Res 41(2):1294–1306. https://doi.org/10.1093/nar/gks1188

    Article  CAS  PubMed  Google Scholar 

  168. Shi M, Zhang H, Wu X, He Z, Wang L, Yin S, Tian B, Li G, Cheng H (2017) ALYREF mainly binds to the 5’ and the 3’ regions of the mRNA in vivo. Nucleic Acids Res 45(16):9640–9653. https://doi.org/10.1093/nar/gkx597

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  169. Izaurralde E, Lewis J, Gamberi C, Jarmolowski A, McGuigan C, Mattaj IW (1995) A cap-binding protein complex mediating U snRNA export. Nature 376(6542):709–712. https://doi.org/10.1038/376709a0

    Article  CAS  PubMed  Google Scholar 

  170. Cheng H, Dufu K, Lee CS, Hsu JL, Dias A, Reed R (2006) Human mRNA export machinery recruited to the 5’ end of mRNA. Cell 127(7):1389–1400. https://doi.org/10.1016/j.cell.2006.10.044

    Article  CAS  PubMed  Google Scholar 

  171. Dias SM, Cerione RA, Wilson KF (2010) Unloading RNAs in the cytoplasm: an “importin” task. Nucleus 1(2):139–143. https://doi.org/10.4161/nucl.1.2.10919

    Article  PubMed  Google Scholar 

  172. Maquat LE, Tarn WY, Isken O (2010) The pioneer round of translation: features and functions. Cell 142(3):368–374. https://doi.org/10.1016/j.cell.2010.07.022

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  173. Le Hir H, Izaurralde E, Maquat LE, Moore MJ (2000) The spliceosome deposits multiple proteins 20–24 nucleotides upstream of mRNA exon-exon junctions. EMBO J 19(24):6860–6869. https://doi.org/10.1093/emboj/19.24.6860

    Article  PubMed  PubMed Central  Google Scholar 

  174. Nott A, Le Hir H, Moore MJ (2004) Splicing enhances translation in mammalian cells: an additional function of the exon junction complex. Genes Dev 18(2):210–222. https://doi.org/10.1101/gad.1163204

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  175. Proudfoot N (2004) New perspectives on connecting messenger RNA 3’ end formation to transcription. Curr Opin Cell Biol 16(3):272–278. https://doi.org/10.1016/j.ceb.2004.03.007

    Article  CAS  PubMed  Google Scholar 

  176. Fuke H, Ohno M (2008) Role of poly (A) tail as an identity element for mRNA nuclear export. Nucleic Acids Res 36(3):1037–1049. https://doi.org/10.1093/nar/gkm1120

    Article  CAS  PubMed  Google Scholar 

  177. Taniguchi I, Ohno M (2008) ATP-dependent recruitment of export factor Aly/REF onto intronless mRNAs by RNA helicase UAP56. Mol Cell Biol 28(2):601–608. https://doi.org/10.1128/MCB.01341-07

    Article  CAS  PubMed  Google Scholar 

  178. Flaherty SM, Fortes P, Izaurralde E, Mattaj IW, Gilmartin GM (1997) Participation of the nuclear cap binding complex in pre-mRNA 3’ processing. Proc Natl Acad Sci USA 94(22):11893–11898

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  179. Visa N, Alzhanova-Ericsson AT, Sun X, Kiseleva E, Bjorkroth B, Wurtz T, Daneholt B (1996) A pre-mRNA-binding protein accompanies the RNA from the gene through the nuclear pores and into polysomes. Cell 84(2):253–264

    Article  CAS  PubMed  Google Scholar 

  180. Visa N, Izaurralde E, Ferreira J, Daneholt B, Mattaj IW (1996) A nuclear cap-binding complex binds Balbiani ring pre-mRNA cotranscriptionally and accompanies the ribonucleoprotein particle during nuclear export. J Cell Biol 133(1):5–14

    Article  CAS  PubMed  Google Scholar 

  181. Daneholt B (1997) A look at messenger RNP moving through the nuclear pore. Cell 88(5):585–588

    Article  CAS  PubMed  Google Scholar 

  182. Daneholt B (2001) Assembly and transport of a premessenger RNP particle. Proc Natl Acad Sci USA 98(13):7012–7017. https://doi.org/10.1073/pnas.111145498

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  183. Veith R, Sorkalla T, Baumgart E, Anzt J, Haberlein H, Tyagi S, Siebrasse JP, Kubitscheck U (2010) Balbiani ring mRNPs diffuse through and bind to clusters of large intranuclear molecular structures. Biophys J 99(8):2676–2685. https://doi.org/10.1016/j.bpj.2010.08.004

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  184. Fribourg S, Braun IC, Izaurralde E, Conti E (2001) Structural basis for the recognition of a nucleoporin FG repeat by the NTF2-like domain of the TAP/p15 mRNA nuclear export factor. Mol Cell 8(3):645–656

    Article  CAS  PubMed  Google Scholar 

  185. Braun IC, Herold A, Rode M, Izaurralde E (2002) Nuclear export of mRNA by TAP/NXF1 requires two nucleoporin-binding sites but not p15. Mol Cell Biol 22(15):5405–5418

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  186. Grant RP, Hurt E, Neuhaus D, Stewart M (2002) Structure of the C-terminal FG-nucleoporin binding domain of Tap/NXF1. Nat Struct Biol 9(4):247–251. https://doi.org/10.1038/nsb773

    Article  CAS  PubMed  Google Scholar 

  187. Blobel G (1985) Gene gating: a hypothesis. Proc Natl Acad Sci USA 82(24):8527–8529

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  188. Agutter PS (1994) Models for solid-state transport: messenger RNA movement from nucleus to cytoplasm. Cell Biol Int 18(9):849–858. https://doi.org/10.1006/cbir.1994.1121

    Article  CAS  PubMed  Google Scholar 

  189. Colon-Ramos DA, Salisbury JL, Sanders MA, Shenoy SM, Singer RH, Garcia-Blanco MA (2003) Asymmetric distribution of nuclear pore complexes and the cytoplasmic localization of beta2-tubulin mRNA in Chlamydomonas reinhardtii. Dev Cell 4(6):941–952

    Article  CAS  PubMed  Google Scholar 

  190. Casolari JM, Brown CR, Komili S, West J, Hieronymus H, Silver PA (2004) Genome-wide localization of the nuclear transport machinery couples transcriptional status and nuclear organization. Cell 117(4):427–439

    Article  CAS  PubMed  Google Scholar 

  191. Bridger JM, Kalla C, Wodrich H, Weitz S, King JA, Khazaie K, Krausslich HG, Lichter P (2005) Nuclear RNAs confined to a reticular compartment between chromosome territories. Exp Cell Res 302(2):180–193. https://doi.org/10.1016/j.yexcr.2004.07.038

    Article  CAS  PubMed  Google Scholar 

  192. Vargas DY, Raj A, Marras SA, Kramer FR, Tyagi S (2005) Mechanism of mRNA transport in the nucleus. Proc Natl Acad Sci USA 102(47):17008–17013. https://doi.org/10.1073/pnas.0505580102

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  193. Frey S, Gorlich D (2009) FG/FxFG as well as GLFG repeats form a selective permeability barrier with self-healing properties. EMBO J 28(17):2554–2567. https://doi.org/10.1038/emboj.2009.199

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  194. Knockenhauer KE, Schwartz TU (2016) The nuclear pore complex as a flexible and dynamic gate. Cell 164(6):1162–1171. https://doi.org/10.1016/j.cell.2016.01.034

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  195. Schmitt C, von Kobbe C, Bachi A, Pante N, Rodrigues JP, Boscheron C, Rigaut G, Wilm M, Seraphin B, Carmo-Fonseca M, Izaurralde E (1999) Dbp5, a DEAD-box protein required for mRNA export, is recruited to the cytoplasmic fibrils of nuclear pore complex via a conserved interaction with CAN/Nup159p. EMBO J 18(15):4332–4347. https://doi.org/10.1093/emboj/18.15.4332

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  196. Hodge CA, Colot HV, Stafford P, Cole CN (1999) Rat8p/Dbp5p is a shuttling transport factor that interacts with Rat7p/Nup159p and Gle1p and suppresses the mRNA export defect of xpo1-1 cells. EMBO J 18(20):5778–5788. https://doi.org/10.1093/emboj/18.20.5778

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  197. Lund MK, Guthrie C (2005) The DEAD-box protein Dbp5p is required to dissociate Mex67p from exported mRNPs at the nuclear rim. Mol Cell 20(4):645–651. https://doi.org/10.1016/j.molcel.2005.10.005

    Article  CAS  PubMed  Google Scholar 

  198. Napetschnig J, Kassube SA, Debler EW, Wong RW, Blobel G, Hoelz A (2009) Structural and functional analysis of the interaction between the nucleoporin Nup214 and the DEAD-box helicase Ddx19. Proc Natl Acad Sci USA 106(9):3089–3094. https://doi.org/10.1073/pnas.0813267106

    Article  PubMed  PubMed Central  Google Scholar 

  199. von Moeller H, Basquin C, Conti E (2009) The mRNA export protein DBP5 binds RNA and the cytoplasmic nucleoporin NUP214 in a mutually exclusive manner. Nat Struct Mol Biol 16(3):247–254. https://doi.org/10.1038/nsmb.1561

    Article  CAS  Google Scholar 

  200. Folkmann AW, Collier SE, Zhan X, Aditi Ohi MD, Wente SR (2013) Gle1 functions during mRNA export in an oligomeric complex that is altered in human disease. Cell 155(3):582–593. https://doi.org/10.1016/j.cell.2013.09.023

    Article  CAS  PubMed  Google Scholar 

  201. Adams RL, Mason AC, Glass L, Aditi Wente SR (2017) Nup42 and IP6 coordinate Gle1 stimulation of Dbp5/DDX19B for mRNA export in yeast and human cells. Traffic 18(12):776–790. https://doi.org/10.1111/tra.12526

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  202. Lin DH, Correia AR, Cai SW, Huber FM, Jette CA, Hoelz A (2018) Structural and functional analysis of mRNA export regulation by the nuclear pore complex. Nat Commun 9(1):2319. https://doi.org/10.1038/s41467-018-04459-3

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  203. Weirich CS, Erzberger JP, Flick JS, Berger JM, Thorner J, Weis K (2006) Activation of the DExD/H-box protein Dbp5 by the nuclear-pore protein Gle1 and its coactivator InsP6 is required for mRNA export. Nat Cell Biol 8(7):668–676. https://doi.org/10.1038/ncb1424

    Article  CAS  PubMed  Google Scholar 

  204. Tran EJ, Zhou Y, Corbett AH, Wente SR (2007) The DEAD-box protein Dbp5 controls mRNA export by triggering specific RNA: protein remodeling events. Mol Cell 28(5):850–859. https://doi.org/10.1016/j.molcel.2007.09.019

    Article  CAS  PubMed  Google Scholar 

  205. Siebrasse JP, Kaminski T, Kubitscheck U (2012) Nuclear export of single native mRNA molecules observed by light sheet fluorescence microscopy. Proc Natl Acad Sci USA 109(24):9426–9431. https://doi.org/10.1073/pnas.1201781109

    Article  PubMed  PubMed Central  Google Scholar 

  206. Smith C, Lari A, Derrer CP, Ouwehand A, Rossouw A, Huisman M, Dange T, Hopman M, Joseph A, Zenklusen D, Weis K, Grunwald D, Montpetit B (2015) In vivo single-particle imaging of nuclear mRNA export in budding yeast demonstrates an essential role for Mex67p. J Cell Biol 211(6):1121–1130. https://doi.org/10.1083/jcb.201503135

    Article  PubMed  PubMed Central  Google Scholar 

  207. Grunwald D, Singer RH (2010) In vivo imaging of labelled endogenous beta-actin mRNA during nucleocytoplasmic transport. Nature 467(7315):604–607. https://doi.org/10.1038/nature09438

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  208. Ma J, Liu Z, Michelotti N, Pitchiaya S, Veerapaneni R, Androsavich JR, Walter NG, Yang W (2013) High-resolution three-dimensional mapping of mRNA export through the nuclear pore. Nat Commun 4:2414. https://doi.org/10.1038/ncomms3414

    Article  CAS  PubMed  Google Scholar 

  209. Chiu SY, Lejeune F, Ranganathan AC, Maquat LE (2004) The pioneer translation initiation complex is functionally distinct from but structurally overlaps with the steady-state translation initiation complex. Genes Dev 18(7):745–754. https://doi.org/10.1101/gad.1170204

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  210. Maquat LE, Hwang J, Sato H, Tang Y (2010) CBP80-promoted mRNP rearrangements during the pioneer round of translation, nonsense-mediated mRNA decay, and thereafter. Cold Spring Harb Symp Quant Biol 75:127–134. https://doi.org/10.1101/sqb.2010.75.028

    Article  CAS  PubMed  Google Scholar 

  211. Gross T, Siepmann A, Sturm D, Windgassen M, Scarcelli JJ, Seedorf M, Cole CN, Krebber H (2007) The DEAD-box RNA helicase Dbp5 functions in translation termination. Science 315(5812):646–649. https://doi.org/10.1126/science.1134641

    Article  CAS  PubMed  Google Scholar 

  212. Bolger TA, Folkmann AW, Tran EJ, Wente SR (2008) The mRNA export factor Gle1 and inositol hexakisphosphate regulate distinct stages of translation. Cell 134(4):624–633. https://doi.org/10.1016/j.cell.2008.06.027

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  213. Gorlich D, Kraft R, Kostka S, Vogel F, Hartmann E, Laskey RA, Mattaj IW, Izaurralde E (1996) Importin provides a link between nuclear protein import and U snRNA export. Cell 87(1):21–32

    Article  CAS  PubMed  Google Scholar 

  214. Sato H, Maquat LE (2009) Remodeling of the pioneer translation initiation complex involves translation and the karyopherin importin beta. Genes Dev 23(21):2537–2550. https://doi.org/10.1101/gad.1817109

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  215. Dias SM, Wilson KF, Rojas KS, Ambrosio AL, Cerione RA (2009) The molecular basis for the regulation of the cap-binding complex by the importins. Nat Struct Mol Biol 16(9):930–937. https://doi.org/10.1038/nsmb.1649

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  216. Usuki F, Yamashita A, Kashima I, Higuchi I, Osame M, Ohno S (2006) Specific inhibition of nonsense-mediated mRNA decay components, SMG-1 or Upf1, rescues the phenotype of Ullrich disease fibroblasts. Mol Ther 14(3):351–360. https://doi.org/10.1016/j.ymthe.2006.04.011

    Article  CAS  PubMed  Google Scholar 

  217. Kashima I, Yamashita A, Izumi N, Kataoka N, Morishita R, Hoshino S, Ohno M, Dreyfuss G, Ohno S (2006) Binding of a novel SMG-1-Upf1-eRF1-eRF3 complex (SURF) to the exon junction complex triggers Upf1 phosphorylation and nonsense-mediated mRNA decay. Genes Dev 20(3):355–367. https://doi.org/10.1101/gad.1389006

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  218. Isken O, Maquat LE (2008) The multiple lives of NMD factors: balancing roles in gene and genome regulation. Nat Rev Genet 9(9):699–712. https://doi.org/10.1038/nrg2402

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  219. Woeller CF, Gaspari M, Isken O, Maquat LE (2008) NMD resulting from encephalomyocarditis virus IRES-directed translation initiation seems to be restricted to CBP80/20-bound mRNA. EMBO Rep 9(5):446–451. https://doi.org/10.1038/embor.2008.36

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  220. Gehring NH, Lamprinaki S, Kulozik AE, Hentze MW (2009) Disassembly of exon junction complexes by PYM. Cell 137(3):536–548. https://doi.org/10.1016/j.cell.2009.02.042

    Article  CAS  PubMed  Google Scholar 

  221. Wilson KF, Fortes P, Singh US, Ohno M, Mattaj IW, Cerione RA (1999) The nuclear cap-binding complex is a novel target of growth factor receptor-coupled signal transduction. J Biol Chem 274(7):4166–4173

    Article  CAS  PubMed  Google Scholar 

  222. Wilson KF, Wu WJ, Cerione RA (2000) Cdc42 stimulates RNA splicing via the S6 kinase and a novel S6 kinase target, the nuclear cap-binding complex. J Biol Chem 275(48):37307–37310. https://doi.org/10.1074/jbc.C000482200

    Article  CAS  PubMed  Google Scholar 

  223. Ly TK, Wang J, Pereira R, Rojas KS, Peng X, Feng Q, Cerione RA, Wilson KF (2010) Activation of the Ran GTPase is subject to growth factor regulation and can give rise to cellular transformation. J Biol Chem 285(8):5815–5826. https://doi.org/10.1074/jbc.M109.071886

    Article  CAS  PubMed  Google Scholar 

  224. Brennan CM, Gallouzi IE, Steitz JA (2000) Protein ligands to HuR modulate its interaction with target mRNAs in vivo. J Cell Biol 151(1):1–14

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  225. Yang J, Bogerd HP, Wang PJ, Page DC, Cullen BR (2001) Two closely related human nuclear export factors utilize entirely distinct export pathways. Mol Cell 8(2):397–406

    Article  CAS  PubMed  Google Scholar 

  226. Culjkovic B, Topisirovic I, Skrabanek L, Ruiz-Gutierrez M, Borden KL (2006) eIF4E is a central node of an RNA regulon that governs cellular proliferation. J Cell Biol 175(3):415–426. https://doi.org/10.1083/jcb.200607020

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  227. Prechtel AT, Chemnitz J, Schirmer S, Ehlers C, Langbein-Detsch I, Stulke J, Dabauvalle MC, Kehlenbach RH, Hauber J (2006) Expression of CD83 is regulated by HuR via a novel cis-active coding region RNA element. J Biol Chem 281(16):10912–10925. https://doi.org/10.1074/jbc.M510306200

    Article  CAS  PubMed  Google Scholar 

  228. Topisirovic I, Siddiqui N, Lapointe VL, Trost M, Thibault P, Bangeranye C, Pinol-Roma S, Borden KL (2009) Molecular dissection of the eukaryotic initiation factor 4E (eIF4E) export-competent RNP. EMBO J 28(8):1087–1098. https://doi.org/10.1038/emboj.2009.53

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  229. Ciufo LF, Brown JD (2000) Nuclear export of yeast signal recognition particle lacking Srp54p by the Xpo1p/Crm1p NES-dependent pathway. Curr Biol 10(20):1256–1264

    Article  CAS  PubMed  Google Scholar 

  230. Grosshans H, Deinert K, Hurt E, Simos G (2001) Biogenesis of the signal recognition particle (SRP) involves import of SRP proteins into the nucleolus, assembly with the SRP-RNA, and Xpo1p-mediated export. J Cell Biol 153(4):745–762

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  231. Costa EA, Subramanian K, Nunnari J, Weissman JS (2018) Defining the physiological role of SRP in protein-targeting efficiency and specificity. Science 359(6376):689–692. https://doi.org/10.1126/science.aar3607

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  232. Alavian CN, Politz JC, Lewandowski LB, Powers CM, Pederson T (2004) Nuclear export of signal recognition particle RNA in mammalian cells. Biochem Biophys Res Commun 313(2):351–355

    Article  CAS  PubMed  Google Scholar 

  233. Takeiwa T, Taniguchi I, Ohno M (2015) Exportin-5 mediates nuclear export of SRP RNA in vertebrates. Genes Cells 20(4):281–291. https://doi.org/10.1111/gtc.12218

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  234. Mahadevan K, Zhang H, Akef A, Cui XA, Gueroussov S, Cenik C, Roth FP, Palazzo AF (2013) RanBP2/Nup358 potentiates the translation of a subset of mRNAs encoding secretory proteins. PLoS Biol 11(4):e1001545. https://doi.org/10.1371/journal.pbio.1001545

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  235. Kassube SA, Stuwe T, Lin DH, Antonuk CD, Napetschnig J, Blobel G, Hoelz A (2012) Crystal structure of the N-terminal domain of Nup358/RanBP2. J Mol Biol 423(5):752–765. https://doi.org/10.1016/j.jmb.2012.08.026

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  236. Palazzo AF, Springer M, Shibata Y, Lee CS, Dias AP, Rapoport TA (2007) The signal sequence coding region promotes nuclear export of mRNA. PLoS Biol 5(12):e322. https://doi.org/10.1371/journal.pbio.0050322

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  237. Ferreira PA, Nakayama TA, Pak WL, Travis GH (1996) Cyclophilin-related protein RanBP2 acts as chaperone for red/green opsin. Nature 383(6601):637–640

    Article  CAS  PubMed  Google Scholar 

  238. Ferreira PA, Nakayama TA, Travis GH (1997) Interconversion of red opsin isoforms by the cyclophilin-related chaperone protein Ran-binding protein 2. Proc Natl Acad Sci USA 94(4):1556–1561

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  239. Cho KI, Patil H, Senda E, Wang J, Yi H, Qiu S, Yoon D, Yu M, Orry A, Peachey NS, Ferreira PA (2014) Differential loss of prolyl isomerase or chaperone activity of Ran-binding protein 2 (Ranbp2) unveils distinct physiological roles of its cyclophilin domain in proteostasis. J Biol Chem 289(8):4600–4625. https://doi.org/10.1074/jbc.M113.538215

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  240. Cho KI, Orry A, Park SE, Ferreira PA (2015) Targeting the cyclophilin domain of Ran-binding protein 2 (Ranbp2) with novel small molecules to control the proteostasis of STAT3, hnRNPA2B1 and M-Opsin. ACS Chem Neurosci 6(8):1476–1485. https://doi.org/10.1021/acschemneuro.5b00134

    Article  CAS  PubMed  Google Scholar 

  241. Cho KI, Yoon D, Qiu S, Danziger Z, Grill WM, Wetsel WC, Ferreira PA (2017) Loss of Ranbp2 in motoneurons causes disruption of nucleocytoplasmic and chemokine signaling, proteostasis of hnRNPH3 and Mmp28, and development of amyotrophic lateral sclerosis-like syndromes. Dis Model Mech 10(5):559–579. https://doi.org/10.1242/dmm.027730

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  242. Culjkovic-Kraljacic B, Baguet A, Volpon L, Amri A, Borden KL (2012) The oncogene eIF4E reprograms the nuclear pore complex to promote mRNA export and oncogenic transformation. Cell Rep 2(2):207–215. https://doi.org/10.1016/j.celrep.2012.07.007

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  243. Hamada M, Haeger A, Jeganathan KB, van Ree JH, Malureanu L, Walde S, Joseph J, Kehlenbach RH, van Deursen JM (2011) Ran-dependent docking of importin-beta to RanBP2/Nup358 filaments is essential for protein import and cell viability. J Cell Biol 194(4):597–612. https://doi.org/10.1083/jcb.201102018

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  244. Hutten S, Kehlenbach RH (2006) Nup214 is required for CRM1-dependent nuclear protein export in vivo. Mol Cell Biol 26(18):6772–6785

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  245. Patil H, Saha A, Senda E, Cho KI, Haque M, Yu M, Qiu S, Yoon D, Hao Y, Peachey NS, Ferreira PA (2014) Selective impairment of a subset of Ran-GTP-binding domains of Ran-binding protein 2 (Ranbp2) suffices to recapitulate the degeneration of the retinal pigment epithelium (RPE) triggered by Ranbp2 ablation. J Biol Chem 298:29767–29789. https://doi.org/10.1074/jbc.M114.586834

    Article  CAS  Google Scholar 

  246. Wickramasinghe VO, McMurtrie PI, Mills AD, Takei Y, Penrhyn-Lowe S, Amagase Y, Main S, Marr J, Stewart M, Laskey RA (2010) mRNA export from mammalian cell nuclei is dependent on GANP. Curr Biol 20(1):25–31. https://doi.org/10.1016/j.cub.2009.10.078

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  247. Jani D, Lutz S, Hurt E, Laskey RA, Stewart M, Wickramasinghe VO (2012) Functional and structural characterization of the mammalian TREX-2 complex that links transcription with nuclear messenger RNA export. Nucleic Acids Res 40(10):4562–4573. https://doi.org/10.1093/nar/gks059

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  248. Singh SK, Maeda K, Eid MM, Almofty SA, Ono M, Pham P, Goodman MF, Sakaguchi N (2013) GANP regulates recruitment of AID to immunoglobulin variable regions by modulating transcription and nucleosome occupancy. Nat Commun 4:1830. https://doi.org/10.1038/ncomms2823

    Article  CAS  PubMed  Google Scholar 

  249. Smith DH (2009) Stretch growth of integrated axon tracts: extremes and exploitations. Prog Neurobiol 89(3):231–239. https://doi.org/10.1016/j.pneurobio.2009.07.006

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  250. Anden NE, Hfuxe K, Hamberger B, Hokfelt T (1966) A quantitative study on the nigro-neostriatal dopamine neuron system in the rat. Acta Physiol Scand 67(3):306–312. https://doi.org/10.1111/j.1748-1716.1966.tb03317.x

    Article  CAS  PubMed  Google Scholar 

  251. Matsuda W, Furuta T, Nakamura KC, Hioki H, Fujiyama F, Arai R, Kaneko T (2009) Single nigrostriatal dopaminergic neurons form widely spread and highly dense axonal arborizations in the neostriatum. J Neurosci 29(2):444–453. https://doi.org/10.1523/JNEUROSCI.4029-08.2009

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  252. Cai Y, Singh BB, Aslanukov A, Zhao H, Ferreira PA (2001) The docking of kinesins, KIF5B and KIF5C, to Ran-binding protein 2 (RanBP2) is mediated via a novel RanBP2 domain. J Biol Chem 276(45):41594–41602

    Article  CAS  PubMed  Google Scholar 

  253. Cho KI, Yi H, Desai R, Hand AR, Haas AL, Ferreira PA (2009) RANBP2 is an allosteric activator of the conventional kinesin-1 motor protein, KIF5B, in a minimal cell-free system. EMBO Rep 10(5):480–486. https://doi.org/10.1038/embor.2009.29

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  254. Patil H, Cho KI, Lee J, Yang Y, Orry A, Ferreira PA (2013) Kinesin-1 and mitochondrial motility control by discrimination of structurally equivalent but distinct subdomains in Ran-GTP-binding domains of Ran-binding protein 2. Open Biol 3(3):120183. https://doi.org/10.1098/rsob.120183

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  255. Mavlyutov TA, Cai Y, Ferreira PA (2002) Identification of RanBP2- and kinesin-mediated transport pathways with restricted neuronal and subcellular localization. Traffic 3(9):630–640

    Article  CAS  PubMed  Google Scholar 

  256. D’Angelo MA, Raices M, Panowski SH, Hetzer MW (2009) Age-dependent deterioration of nuclear pore complexes causes a loss of nuclear integrity in postmitotic cells. Cell 136(2):284–295. https://doi.org/10.1016/j.cell.2008.11.037

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  257. Kanai Y, Dohmae N, Hirokawa N (2004) Kinesin transports RNA: isolation and characterization of an RNA-transporting granule. Neuron 43(4):513–525

    Article  CAS  PubMed  Google Scholar 

  258. Diefenbach RJ, Diefenbach E, Douglas MW, Cunningham AL (2004) The ribosome receptor, p180, interacts with kinesin heavy chain, KIF5B. Biochem Biophys Res Commun 319(3):987–992

    Article  CAS  PubMed  Google Scholar 

  259. Ling SC, Fahrner PS, Greenough WT, Gelfand VI (2004) Transport of Drosophila fragile X mental retardation protein-containing ribonucleoprotein granules by kinesin-1 and cytoplasmic dynein. Proc Natl Acad Sci USA 101(50):17428–17433. https://doi.org/10.1073/pnas.0408114101

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  260. Jeong JH, Nam YJ, Kim SY, Kim EG, Jeong J, Kim HK (2007) The transport of Staufen2-containing ribonucleoprotein complexes involves kinesin motor protein and is modulated by mitogen-activated protein kinase pathway. J Neurochem 102(6):2073–2084. https://doi.org/10.1111/j.1471-4159.2007.04697.x

    Article  CAS  PubMed  Google Scholar 

  261. Palacios IM, Gatfield D, St Johnston D, Izaurralde E (2004) An eIF4AIII-containing complex required for mRNA localization and nonsense-mediated mRNA decay. Nature 427(6976):753–757. https://doi.org/10.1038/nature02351

    Article  CAS  PubMed  Google Scholar 

  262. Shibuya T, Tange TO, Sonenberg N, Moore MJ (2004) eIF4AIII binds spliced mRNA in the exon junction complex and is essential for nonsense-mediated decay. Nat Struct Mol Biol 11(4):346–351. https://doi.org/10.1038/nsmb750

    Article  CAS  PubMed  Google Scholar 

  263. Giorgi C, Yeo GW, Stone ME, Katz DB, Burge C, Turrigiano G, Moore MJ (2007) The EJC factor eIF4AIII modulates synaptic strength and neuronal protein expression. Cell 130(1):179–191. https://doi.org/10.1016/j.cell.2007.05.028

    Article  CAS  PubMed  Google Scholar 

  264. Hanz S, Perlson E, Willis D, Zheng JQ, Massarwa R, Huerta JJ, Koltzenburg M, Kohler M, van-Minnen J, Twiss JL, Fainzilber M (2003) Axoplasmic importins enable retrograde injury signaling in lesioned nerve. Neuron 40(6):1095–1104

    Article  CAS  PubMed  Google Scholar 

  265. Perry RB, Doron-Mandel E, Iavnilovitch E, Rishal I, Dagan SY, Tsoory M, Coppola G, McDonald MK, Gomes C, Geschwind DH, Twiss JL, Yaron A, Fainzilber M (2012) Subcellular knockout of importin beta1 perturbs axonal retrograde signaling. Neuron 75(2):294–305. https://doi.org/10.1016/j.neuron.2012.05.033

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  266. Yudin D, Hanz S, Yoo S, Iavnilovitch E, Willis D, Gradus T, Vuppalanchi D, Segal-Ruder Y, Ben-Yaakov K, Hieda M, Yoneda Y, Twiss JL, Fainzilber M (2008) Localized regulation of axonal RanGTPase controls retrograde injury signaling in peripheral nerve. Neuron 59(2):241–252. https://doi.org/10.1016/j.neuron.2008.05.029

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  267. Ben-Yaakov K, Dagan SY, Segal-Ruder Y, Shalem O, Vuppalanchi D, Willis DE, Yudin D, Rishal I, Rother F, Bader M, Blesch A, Pilpel Y, Twiss JL, Fainzilber M (2012) Axonal transcription factors signal retrogradely in lesioned peripheral nerve. EMBO J 31(6):1350–1363. https://doi.org/10.1038/emboj.2011.494

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  268. Twiss JL, Fainzilber M (2009) Ribosomes in axons–scrounging from the neighbors? Trends Cell Biol 19(5):236–243. https://doi.org/10.1016/j.tcb.2009.02.007

    Article  CAS  PubMed  Google Scholar 

  269. Colak D, Ji SJ, Porse BT, Jaffrey SR (2013) Regulation of axon guidance by compartmentalized nonsense-mediated mRNA decay. Cell 153(6):1252–1265. https://doi.org/10.1016/j.cell.2013.04.056

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  270. Shigeoka T, Jung H, Jung J, Turner-Bridger B, Ohk J, Lin JQ, Amieux PS, Holt CE (2016) Dynamic axonal translation in developing and mature visual circuits. Cell 166(1):181–192. https://doi.org/10.1016/j.cell.2016.05.029

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  271. Wong HH, Lin JQ, Strohl F, Roque CG, Cioni JM, Cagnetta R, Turner-Bridger B, Laine RF, Harris WA, Kaminski CF, Holt CE (2017) RNA docking and local translation regulate site-specific axon remodeling in vivo. Neuron 95(4):852 e858–868 e858. https://doi.org/10.1016/j.neuron.2017.07.016

    Article  CAS  Google Scholar 

  272. Bellon A, Iyer A, Bridi S, Lee FCY, Ovando-Vazquez C, Corradi E, Longhi S, Roccuzzo M, Strohbuecker S, Naik S, Sarkies P, Miska E, Abreu-Goodger C, Holt CE, Baudet ML (2017) miR-182 Regulates Slit2-mediated axon guidance by modulating the local translation of a specific mRNA. Cell Rep 18(5):1171–1186. https://doi.org/10.1016/j.celrep.2016.12.093

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  273. Cho KI, Yi H, Yeh A, Tserentsoodol N, Cuadrado L, Searle K, Hao Y, Ferreira PA (2009) Haploinsufficiency of RanBP2 is neuroprotective against light-elicited and age-dependent degeneration of photoreceptor neurons. Cell Death Differ 16(2):287–297. https://doi.org/10.1038/cdd.2008.153

    Article  CAS  PubMed  Google Scholar 

  274. Cho KI, Yi H, Tserentsoodol N, Searle K, Ferreira PA (2010) Neuroprotection resulting from insufficiency of RANBP2 is associated with the modulation of protein and lipid homeostasis of functionally diverse but linked pathways in response to oxidative stress. Dis Model Mech 3(9–10):595–604. https://doi.org/10.1242/dmm.004648

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  275. Jiang K, Wright KL, Zhu P, Szego MJ, Bramall AN, Hauswirth WW, Li Q, Egan SE, McInnes RR (2014) STAT3 promotes survival of mutant photoreceptors in inherited photoreceptor degeneration models. Proc Natl Acad Sci USA 111(52):E5716–E5723. https://doi.org/10.1073/pnas.1411248112

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  276. Da Cruz S, Bui A, Saberi S, Lee SK, Stauffer J, McAlonis-Downes M, Schulte D, Pizzo DP, Parone PA, Cleveland DW, Ravits J (2017) Misfolded SOD1 is not a primary component of sporadic ALS. Acta Neuropathol 134(1):97–111. https://doi.org/10.1007/s00401-017-1688-8

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  277. Sareen D, O’Rourke JG, Meera P, Muhammad AK, Grant S, Simpkinson M, Bell S, Carmona S, Ornelas L, Sahabian A, Gendron T, Petrucelli L, Baughn M, Ravits J, Harms MB, Rigo F, Bennett CF, Otis TS, Svendsen CN, Baloh RH (2013) Targeting RNA foci in iPSC-derived motor neurons from ALS patients with a C9ORF72 repeat expansion. Sci Transl Med 5(208):208ra149. https://doi.org/10.1126/scitranslmed.3007529

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  278. Jovicic A, Mertens J, Boeynaems S, Bogaert E, Chai N, Yamada SB, Paul JW 3rd, Sun S, Herdy JR, Bieri G, Kramer NJ, Gage FH, Van Den Bosch L, Robberecht W, Gitler AD (2015) Modifiers of C9orf72 dipeptide repeat toxicity connect nucleocytoplasmic transport defects to FTD/ALS. Nat Neurosci 18(9):1226–1229. https://doi.org/10.1038/nn.4085

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  279. Boeynaems S, Bogaert E, Michiels E, Gijselinck I, Sieben A, Jovicic A, De Baets G, Scheveneels W, Steyaert J, Cuijt I, Verstrepen KJ, Callaerts P, Rousseau F, Schymkowitz J, Cruts M, Van Broeckhoven C, Van Damme P, Gitler AD, Robberecht W, Van Den Bosch L (2016) Drosophila screen connects nuclear transport genes to DPR pathology in c9ALS/FTD. Sci Rep 6:20877. https://doi.org/10.1038/srep20877

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  280. Sreedharan J, Blair IP, Tripathi VB, Hu X, Vance C, Rogelj B, Ackerley S, Durnall JC, Williams KL, Buratti E, Baralle F, de Belleroche J, Mitchell JD, Leigh PN, Al-Chalabi A, Miller CC, Nicholson G, Shaw CE (2008) TDP-43 mutations in familial and sporadic amyotrophic lateral sclerosis. Science 319(5870):1668–1672. https://doi.org/10.1126/science.1154584

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  281. Benajiba L, Le Ber I, Camuzat A, Lacoste M, Thomas-Anterion C, Couratier P, Legallic S, Salachas F, Hannequin D, Decousus M, Lacomblez L, Guedj E, Golfier V, Camu W, Dubois B, Campion D, Meininger V, Brice A, French C, Genetic Research Network on Frontotemporal Lobar Degeneration/Frontotemporal Lobar Degeneration with Motoneuron D (2009) TARDBP mutations in motoneuron disease with frontotemporal lobar degeneration. Ann Neurol 65(4):470–473. https://doi.org/10.1002/ana.21612

    Article  CAS  Google Scholar 

  282. Ou SH, Wu F, Harrich D, Garcia-Martinez LF, Gaynor RB (1995) Cloning and characterization of a novel cellular protein, TDP-43, that binds to human immunodeficiency virus type 1 TAR DNA sequence motifs. J Virol 69(6):3584–3596

    CAS  PubMed  PubMed Central  Google Scholar 

  283. Buratti E, Baralle FE (2001) Characterization and functional implications of the RNA binding properties of nuclear factor TDP-43, a novel splicing regulator of CFTR exon 9. J Biol Chem 276(39):36337–36343. https://doi.org/10.1074/jbc.M104236200

    Article  CAS  PubMed  Google Scholar 

  284. Buratti E, Dork T, Zuccato E, Pagani F, Romano M, Baralle FE (2001) Nuclear factor TDP-43 and SR proteins promote in vitro and in vivo CFTR exon 9 skipping. EMBO J 20(7):1774–1784. https://doi.org/10.1093/emboj/20.7.1774

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  285. Ayala YM, Pagani F, Baralle FE (2006) TDP43 depletion rescues aberrant CFTR exon 9 skipping. FEBS Lett 580(5):1339–1344. https://doi.org/10.1016/j.febslet.2006.01.052

    Article  CAS  PubMed  Google Scholar 

  286. Ayala YM, Zago P, D’Ambrogio A, Xu YF, Petrucelli L, Buratti E, Baralle FE (2008) Structural determinants of the cellular localization and shuttling of TDP-43. J Cell Sci 121(Pt 22):3778–3785. https://doi.org/10.1242/jcs.038950

    Article  CAS  PubMed  Google Scholar 

  287. Winton MJ, Igaz LM, Wong MM, Kwong LK, Trojanowski JQ, Lee VM (2008) Disturbance of nuclear and cytoplasmic TAR DNA-binding protein (TDP-43) induces disease-like redistribution, sequestration, and aggregate formation. J Biol Chem 283(19):13302–13309. https://doi.org/10.1074/jbc.M800342200

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  288. Neumann M, Sampathu DM, Kwong LK, Truax AC, Micsenyi MC, Chou TT, Bruce J, Schuck T, Grossman M, Clark CM, McCluskey LF, Miller BL, Masliah E, Mackenzie IR, Feldman H, Feiden W, Kretzschmar HA, Trojanowski JQ, Lee VM (2006) Ubiquitinated TDP-43 in frontotemporal lobar degeneration and amyotrophic lateral sclerosis. Science 314(5796):130–133. https://doi.org/10.1126/science.1134108

    Article  CAS  PubMed  Google Scholar 

  289. Gitcho MA, Baloh RH, Chakraverty S, Mayo K, Norton JB, Levitch D, Hatanpaa KJ, White CL 3rd, Bigio EH, Caselli R, Baker M, Al-Lozi MT, Morris JC, Pestronk A, Rademakers R, Goate AM, Cairns NJ (2008) TDP-43 A315T mutation in familial motor neuron disease. Ann Neurol 63(4):535–538. https://doi.org/10.1002/ana.21344

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  290. Nonaka T, Kametani F, Arai T, Akiyama H, Hasegawa M (2009) Truncation and pathogenic mutations facilitate the formation of intracellular aggregates of TDP-43. Hum Mol Genet 18(18):3353–3364. https://doi.org/10.1093/hmg/ddp275

    Article  CAS  PubMed  Google Scholar 

  291. Polymenidou M, Lagier-Tourenne C, Hutt KR, Huelga SC, Moran J, Liang TY, Ling SC, Sun E, Wancewicz E, Mazur C, Kordasiewicz H, Sedaghat Y, Donohue JP, Shiue L, Bennett CF, Yeo GW, Cleveland DW (2011) Long pre-mRNA depletion and RNA missplicing contribute to neuronal vulnerability from loss of TDP-43. Nat Neurosci 14(4):459–468. https://doi.org/10.1038/nn.2779

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  292. Ayala YM, De Conti L, Avendano-Vazquez SE, Dhir A, Romano M, D’Ambrogio A, Tollervey J, Ule J, Baralle M, Buratti E, Baralle FE (2011) TDP-43 regulates its mRNA levels through a negative feedback loop. EMBO J 30(2):277–288. https://doi.org/10.1038/emboj.2010.310

    Article  CAS  PubMed  Google Scholar 

  293. Sephton CF, Cenik C, Kucukural A, Dammer EB, Cenik B, Han Y, Dewey CM, Roth FP, Herz J, Peng J, Moore MJ, Yu G (2011) Identification of neuronal RNA targets of TDP-43-containing ribonucleoprotein complexes. J Biol Chem 286(2):1204–1215. https://doi.org/10.1074/jbc.M110.190884

    Article  CAS  PubMed  Google Scholar 

  294. Tollervey JR, Curk T, Rogelj B, Briese M, Cereda M, Kayikci M, Konig J, Hortobagyi T, Nishimura AL, Zupunski V, Patani R, Chandran S, Rot G, Zupan B, Shaw CE, Ule J (2011) Characterizing the RNA targets and position-dependent splicing regulation by TDP-43. Nat Neurosci 14(4):452–458. https://doi.org/10.1038/nn.2778

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  295. Deshaies JE, Shkreta L, Moszczynski AJ, Sidibe H, Semmler S, Fouillen A, Bennett ER, Bekenstein U, Destroismaisons L, Toutant J, Delmotte Q, Volkening K, Stabile S, Aulas A, Khalfallah Y, Soreq H, Nanci A, Strong MJ, Chabot B, Vande Velde C (2018) TDP-43 regulates the alternative splicing of hnRNP A1 to yield an aggregation-prone variant in amyotrophic lateral sclerosis. Brain 141(5):1320–1333. https://doi.org/10.1093/brain/awy062

    Article  PubMed  PubMed Central  Google Scholar 

  296. Fallini C, Bassell GJ, Rossoll W (2012) The ALS disease protein TDP-43 is actively transported in motor neuron axons and regulates axon outgrowth. Hum Mol Genet 21(16):3703–3718. https://doi.org/10.1093/hmg/dds205

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  297. Alami NH, Smith RB, Carrasco MA, Williams LA, Winborn CS, Han SSW, Kiskinis E, Winborn B, Freibaum BD, Kanagaraj A, Clare AJ, Badders NM, Bilican B, Chaum E, Chandran S, Shaw CE, Eggan KC, Maniatis T, Taylor JP (2014) Axonal transport of TDP-43 mRNA granules is impaired by ALS-causing mutations. Neuron 81(3):536–543. https://doi.org/10.1016/j.neuron.2013.12.018

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  298. Fischer LR, Culver DG, Tennant P, Davis AA, Wang M, Castellano-Sanchez A, Khan J, Polak MA, Glass JD (2004) Amyotrophic lateral sclerosis is a distal axonopathy: evidence in mice and man. Exp Neurol 185(2):232–240

    Article  PubMed  Google Scholar 

  299. Nishimura AL, Zupunski V, Troakes C, Kathe C, Fratta P, Howell M, Gallo JM, Hortobagyi T, Shaw CE, Rogelj B (2010) Nuclear import impairment causes cytoplasmic trans-activation response DNA-binding protein accumulation and is associated with frontotemporal lobar degeneration. Brain 133(Pt 6):1763–1771. https://doi.org/10.1093/brain/awq111

    Article  PubMed  Google Scholar 

  300. Archbold HC, Jackson KL, Arora A, Weskamp K, Tank EM, Li X, Miguez R, Dayton RD, Tamir S, Klein RL, Barmada SJ (2018) TDP43 nuclear export and neurodegeneration in models of amyotrophic lateral sclerosis and frontotemporal dementia. Sci Rep 8(1):4606. https://doi.org/10.1038/s41598-018-22858-w

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  301. Barmada SJ, Skibinski G, Korb E, Rao EJ, Wu JY, Finkbeiner S (2010) Cytoplasmic mislocalization of TDP-43 is toxic to neurons and enhanced by a mutation associated with familial amyotrophic lateral sclerosis. J Neurosci 30(2):639–649. https://doi.org/10.1523/JNEUROSCI.4988-09.2010

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  302. Miguel L, Frebourg T, Campion D, Lecourtois M (2011) Both cytoplasmic and nuclear accumulations of the protein are neurotoxic in Drosophila models of TDP-43 proteinopathies. Neurobiol Dis 41(2):398–406. https://doi.org/10.1016/j.nbd.2010.10.007

    Article  CAS  PubMed  Google Scholar 

  303. Ederle H, Funk C, Abou-Ajram C, Hutten S, Funk EBE, Kehlenbach RH, Bailer SM, Dormann D (2018) Nuclear egress of TDP-43 and FUS occurs independently of Exportin-1/CRM1. Sci Rep 8(1):7084. https://doi.org/10.1038/s41598-018-25007-5

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  304. Pinarbasi ES, Cagatay T, Fung HYJ, Li YC, Chook YM, Thomas PJ (2018) Active nuclear import and passive nuclear export are the primary determinants of TDP-43 localization. Sci Rep 8(1):7083. https://doi.org/10.1038/s41598-018-25008-4

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  305. Chou CC, Zhang Y, Umoh ME, Vaughan SW, Lorenzini I, Liu F, Sayegh M, Donlin-Asp PG, Chen YH, Duong DM, Seyfried NT, Powers MA, Kukar T, Hales CM, Gearing M, Cairns NJ, Boylan KB, Dickson DW, Rademakers R, Zhang YJ, Petrucelli L, Sattler R, Zarnescu DC, Glass JD, Rossoll W (2018) TDP-43 pathology disrupts nuclear pore complexes and nucleocytoplasmic transport in ALS/FTD. Nat Neurosci 21(2):228–239. https://doi.org/10.1038/s41593-017-0047-3

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  306. Vance C, Rogelj B, Hortobagyi T, De Vos KJ, Nishimura AL, Sreedharan J, Hu X, Smith B, Ruddy D, Wright P, Ganesalingam J, Williams KL, Tripathi V, Al-Saraj S, Al-Chalabi A, Leigh PN, Blair IP, Nicholson G, de Belleroche J, Gallo JM, Miller CC, Shaw CE (2009) Mutations in FUS, an RNA processing protein, cause familial amyotrophic lateral sclerosis type 6. Science 323(5918):1208–1211. https://doi.org/10.1126/science.1165942

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  307. Kwiatkowski TJ Jr, Bosco DA, Leclerc AL, Tamrazian E, Vanderburg CR, Russ C, Davis A, Gilchrist J, Kasarskis EJ, Munsat T, Valdmanis P, Rouleau GA, Hosler BA, Cortelli P, de Jong PJ, Yoshinaga Y, Haines JL, Pericak-Vance MA, Yan J, Ticozzi N, Siddique T, McKenna-Yasek D, Sapp PC, Horvitz HR, Landers JE, Brown RH Jr (2009) Mutations in the FUS/TLS gene on chromosome 16 cause familial amyotrophic lateral sclerosis. Science 323(5918):1205–1208. https://doi.org/10.1126/science.1166066

    Article  CAS  PubMed  Google Scholar 

  308. Neumann M, Rademakers R, Roeber S, Baker M, Kretzschmar HA, Mackenzie IR (2009) A new subtype of frontotemporal lobar degeneration with FUS pathology. Brain 132(Pt 11):2922–2931. https://doi.org/10.1093/brain/awp214

    Article  PubMed  PubMed Central  Google Scholar 

  309. Kapeli K, Pratt GA, Vu AQ, Hutt KR, Martinez FJ, Sundararaman B, Batra R, Freese P, Lambert NJ, Huelga SC, Chun SJ, Liang TY, Chang J, Donohue JP, Shiue L, Zhang J, Zhu H, Cambi F, Kasarskis E, Hoon S, Ares M Jr, Burge CB, Ravits J, Rigo F, Yeo GW (2016) Distinct and shared functions of ALS-associated proteins TDP-43, FUS and TAF15 revealed by multisystem analyses. Nat Commun 7:12143. https://doi.org/10.1038/ncomms12143

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  310. Fujii R, Takumi T (2005) TLS facilitates transport of mRNA encoding an actin-stabilizing protein to dendritic spines. J Cell Sci 118(Pt 24):5755–5765. https://doi.org/10.1242/jcs.02692

    Article  CAS  PubMed  Google Scholar 

  311. Fujii R, Okabe S, Urushido T, Inoue K, Yoshimura A, Tachibana T, Nishikawa T, Hicks GG, Takumi T (2005) The RNA binding protein TLS is translocated to dendritic spines by mGluR5 activation and regulates spine morphology. Curr Biol 15(6):587–593. https://doi.org/10.1016/j.cub.2005.01.058

    Article  CAS  PubMed  Google Scholar 

  312. Kim HJ, Kim NC, Wang YD, Scarborough EA, Moore J, Diaz Z, MacLea KS, Freibaum B, Li S, Molliex A, Kanagaraj AP, Carter R, Boylan KB, Wojtas AM, Rademakers R, Pinkus JL, Greenberg SA, Trojanowski JQ, Traynor BJ, Smith BN, Topp S, Gkazi AS, Miller J, Shaw CE, Kottlors M, Kirschner J, Pestronk A, Li YR, Ford AF, Gitler AD, Benatar M, King OD, Kimonis VE, Ross ED, Weihl CC, Shorter J, Taylor JP (2013) Mutations in prion-like domains in hnRNPA2B1 and hnRNPA1 cause multisystem proteinopathy and ALS. Nature 495(7442):467–473. https://doi.org/10.1038/nature11922

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  313. Michael WM, Choi M, Dreyfuss G (1995) A nuclear export signal in hnRNP A1: a signal-mediated, temperature-dependent nuclear protein export pathway. Cell 83(3):415–422

    Article  CAS  PubMed  Google Scholar 

  314. Siomi H, Dreyfuss G (1995) A nuclear localization domain in the hnRNP A1 protein. J Cell Biol 129(3):551–560

    Article  CAS  PubMed  Google Scholar 

  315. Izaurralde E, Jarmolowski A, Beisel C, Mattaj IW, Dreyfuss G, Fischer U (1997) A role for the M9 transport signal of hnRNP A1 in mRNA nuclear export. J Cell Biol 137(1):27–35

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  316. Pollard VW, Michael WM, Nakielny S, Siomi MC, Wang F, Dreyfuss G (1996) A novel receptor-mediated nuclear protein import pathway. Cell 86(6):985–994

    Article  CAS  PubMed  Google Scholar 

  317. Munro TP, Magee RJ, Kidd GJ, Carson JH, Barbarese E, Smith LM, Smith R (1999) Mutational analysis of a heterogeneous nuclear ribonucleoprotein A2 response element for RNA trafficking. J Biol Chem 274(48):34389–34395

    Article  CAS  PubMed  Google Scholar 

  318. Hoek KS, Kidd GJ, Carson JH, Smith R (1998) hnRNP A2 selectively binds the cytoplasmic transport sequence of myelin basic protein mRNA. Biochemistry (Mosc) 37(19):7021–7029. https://doi.org/10.1021/bi9800247

    Article  CAS  Google Scholar 

  319. Bekenstein U, Soreq H (2013) Heterogeneous nuclear ribonucleoprotein A1 in health and neurodegenerative disease: from structural insights to post-transcriptional regulatory roles. Mol Cell Neurosci 56:436–446. https://doi.org/10.1016/j.mcn.2012.12.002

    Article  CAS  PubMed  Google Scholar 

  320. Gao Y, Tatavarty V, Korza G, Levin MK, Carson JH (2008) Multiplexed dendritic targeting of alpha calcium calmodulin-dependent protein kinase II, neurogranin, and activity-regulated cytoskeleton-associated protein RNAs by the A2 pathway. Mol Biol Cell 19(5):2311–2327. https://doi.org/10.1091/mbc.E07-09-0914

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  321. Leal G, Afonso PM, Duarte CB (2014) Neuronal activity induces synaptic delivery of hnRNP A2/B1 by a BDNF-dependent mechanism in cultured hippocampal neurons. PLoS One 9(10):e108175. https://doi.org/10.1371/journal.pone.0108175

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  322. Martinez FJ, Pratt GA, Van Nostrand EL, Batra R, Huelga SC, Kapeli K, Freese P, Chun SJ, Ling K, Gelboin-Burkhart C, Fijany L, Wang HC, Nussbacher JK, Broski SM, Kim HJ, Lardelli R, Sundararaman B, Donohue JP, Javaherian A, Lykke-Andersen J, Finkbeiner S, Bennett CF, Ares M Jr, Burge CB, Taylor JP, Rigo F, Yeo GW (2016) Protein-RNA networks regulated by normal and ALS-associated mutant HNRNPA2B1 in the nervous system. Neuron 92(4):780–795. https://doi.org/10.1016/j.neuron.2016.09.050

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  323. Lagier-Tourenne C, Polymenidou M, Hutt KR, Vu AQ, Baughn M, Huelga SC, Clutario KM, Ling SC, Liang TY, Mazur C, Wancewicz E, Kim AS, Watt A, Freier S, Hicks GG, Donohue JP, Shiue L, Bennett CF, Ravits J, Cleveland DW, Yeo GW (2012) Divergent roles of ALS-linked proteins FUS/TLS and TDP-43 intersect in processing long pre-mRNAs. Nat Neurosci 15(11):1488–1497. https://doi.org/10.1038/nn.3230

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  324. Alarcon CR, Goodarzi H, Lee H, Liu X, Tavazoie S, Tavazoie SF (2015) HNRNPA2B1 Is a mediator of m(6)A-dependent nuclear RNA processing events. Cell 162(6):1299–1308. https://doi.org/10.1016/j.cell.2015.08.011

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  325. Villarroya-Beltri C, Gutierrez-Vazquez C, Sanchez-Cabo F, Perez-Hernandez D, Vazquez J, Martin-Cofreces N, Martinez-Herrera DJ, Pascual-Montano A, Mittelbrunn M, Sanchez-Madrid F (2013) Sumoylated hnRNPA2B1 controls the sorting of miRNAs into exosomes through binding to specific motifs. Nat Commun 4:2980. https://doi.org/10.1038/ncomms3980

    Article  CAS  PubMed  Google Scholar 

  326. Nousiainen HO, Kestila M, Pakkasjarvi N, Honkala H, Kuure S, Tallila J, Vuopala K, Ignatius J, Herva R, Peltonen L (2008) Mutations in mRNA export mediator GLE1 result in a fetal motoneuron disease. Nat Genet 40(2):155–157. https://doi.org/10.1038/ng.2007.65

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  327. Kaneb HM, Folkmann AW, Belzil VV, Jao LE, Leblond CS, Girard SL, Daoud H, Noreau A, Rochefort D, Hince P, Szuto A, Levert A, Vidal S, Andre-Guimont C, Camu W, Bouchard JP, Dupre N, Rouleau GA, Wente SR, Dion PA (2015) Deleterious mutations in the essential mRNA metabolism factor, hGle1, in amyotrophic lateral sclerosis. Hum Mol Genet 24(5):1363–1373. https://doi.org/10.1093/hmg/ddu545

    Article  CAS  PubMed  Google Scholar 

  328. Tanaka Y, Kanai Y, Okada Y, Nonaka S, Takeda S, Harada A, Hirokawa N (1998) Targeted disruption of mouse conventional kinesin heavy chain, kif5B, results in abnormal perinuclear clustering of mitochondria. Cell 93(7):1147–1158

    Article  CAS  PubMed  Google Scholar 

  329. Pilling AD, Horiuchi D, Lively CM, Saxton WM (2006) Kinesin-1 and Dynein are the primary motors for fast transport of mitochondria in Drosophila motor axons. Mol Biol Cell 17(4):2057–2068. https://doi.org/10.1091/mbc.E05-06-0526

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  330. Cho KI, Cai Y, Yi H, Yeh A, Aslanukov A, Ferreira PA (2007) Association of the kinesin-binding domain of RanBP2 to KIF5B and KIF5C determines mitochondria localization and function. Traffic 8:1722–1735

    Article  CAS  PubMed  Google Scholar 

  331. Patil H, Yoon D, Bhowmick R, Cai Y, Cho KI, Ferreira PA (2019) Impairments in age-dependent ubiquitin proteostasis and structural integrity of selective neurons by uncoupling Ran GTPase from the Ran-binding domain 3 of Ranbp2 and identification of novel mitochondrial isoforms of ubiquitin-conjugating enzyme E2I (ubc9) and Ranbp2. Small GTPases 10(2):146–161. https://doi.org/10.1080/21541248.2017.1356432

    Article  CAS  PubMed  Google Scholar 

  332. Ohgomori T, Yamasaki R, Takeuchi H, Kadomatsu K, Kira JI, Jinno S (2017) Differential activation of neuronal and glial STAT3 in the spinal cord of the SOD1(G93A) mouse model of amyotrophic lateral sclerosis. Eur J Neurosci 46(4):2001–2014. https://doi.org/10.1111/ejn.13650

    Article  PubMed  Google Scholar 

  333. Bonnin E, Cabochette P, Filosa A, Juhlen R, Komatsuzaki S, Hezwani M, Dickmanns A, Martinelli V, Vermeersch M, Supply L, Martins N, Pirenne L, Ravenscroft G, Lombard M, Port S, Spillner C, Janssens S, Roets E, Van Dorpe J, Lammens M, Kehlenbach RH, Ficner R, Laing NG, Hoffmann K, Vanhollebeke B, Fahrenkrog B (2018) Biallelic mutations in nucleoporin NUP88 cause lethal fetal akinesia deformation sequence. PLoS Genet 14(12):e1007845. https://doi.org/10.1371/journal.pgen.1007845

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  334. Nishimura AL, Mitne-Neto M, Silva HC, Richieri-Costa A, Middleton S, Cascio D, Kok F, Oliveira JR, Gillingwater T, Webb J, Skehel P, Zatz M (2004) A mutation in the vesicle-trafficking protein VAPB causes late-onset spinal muscular atrophy and amyotrophic lateral sclerosis. Am J Hum Genet 75(5):822–831. https://doi.org/10.1086/425287

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  335. Chen HJ, Anagnostou G, Chai A, Withers J, Morris A, Adhikaree J, Pennetta G, de Belleroche JS (2010) Characterization of the properties of a novel mutation in VAPB in familial amyotrophic lateral sclerosis. J Biol Chem 285(51):40266–40281. https://doi.org/10.1074/jbc.M110.161398

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  336. Maruyama H, Morino H, Ito H, Izumi Y, Kato H, Watanabe Y, Kinoshita Y, Kamada M, Nodera H, Suzuki H, Komure O, Matsuura S, Kobatake K, Morimoto N, Abe K, Suzuki N, Aoki M, Kawata A, Hirai T, Kato T, Ogasawara K, Hirano A, Takumi T, Kusaka H, Hagiwara K, Kaji R, Kawakami H (2010) Mutations of optineurin in amyotrophic lateral sclerosis. Nature 465(7295):223–226. https://doi.org/10.1038/nature08971

    Article  CAS  PubMed  Google Scholar 

  337. Del Bo R, Tiloca C, Pensato V, Corrado L, Ratti A, Ticozzi N, Corti S, Castellotti B, Mazzini L, Soraru G, Cereda C, D’Alfonso S, Gellera C, Comi GP, Silani V, Consortium S (2011) Novel optineurin mutations in patients with familial and sporadic amyotrophic lateral sclerosis. J Neurol Neurosurg Psychiatry 82(11):1239–1243. https://doi.org/10.1136/jnnp.2011.242313

    Article  Google Scholar 

  338. Wu CH, Fallini C, Ticozzi N, Keagle PJ, Sapp PC, Piotrowska K, Lowe P, Koppers M, McKenna-Yasek D, Baron DM, Kost JE, Gonzalez-Perez P, Fox AD, Adams J, Taroni F, Tiloca C, Leclerc AL, Chafe SC, Mangroo D, Moore MJ, Zitzewitz JA, Xu ZS, van den Berg LH, Glass JD, Siciliano G, Cirulli ET, Goldstein DB, Salachas F, Meininger V, Rossoll W, Ratti A, Gellera C, Bosco DA, Bassell GJ, Silani V, Drory VE, Brown RH Jr, Landers JE (2012) Mutations in the profilin 1 gene cause familial amyotrophic lateral sclerosis. Nature 488(7412):499–503. https://doi.org/10.1038/nature11280

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  339. Yang C, Danielson EW, Qiao T, Metterville J, Brown RH Jr, Landers JE, Xu Z (2016) Mutant PFN1 causes ALS phenotypes and progressive motor neuron degeneration in mice by a gain of toxicity. Proc Natl Acad Sci USA 113(41):E6209–E6218. https://doi.org/10.1073/pnas.1605964113

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  340. Tran D, Chalhoub A, Schooley A, Zhang W, Ngsee JK (2012) A mutation in VAPB that causes amyotrophic lateral sclerosis also causes a nuclear envelope defect. J Cell Sci 125(Pt 12):2831–2836. https://doi.org/10.1242/jcs.102111

    Article  CAS  PubMed  Google Scholar 

  341. Rezaie T, Child A, Hitchings R, Brice G, Miller L, Coca-Prados M, Heon E, Krupin T, Ritch R, Kreutzer D, Crick RP, Sarfarazi M (2002) Adult-onset primary open-angle glaucoma caused by mutations in optineurin. Science 295(5557):1077–1079. https://doi.org/10.1126/science.1066901

    Article  CAS  PubMed  Google Scholar 

  342. De Marco N, Buono M, Troise F, Diez-Roux G (2006) Optineurin increases cell survival and translocates to the nucleus in a Rab8-dependent manner upon an apoptotic stimulus. J Biol Chem 281(23):16147–16156. https://doi.org/10.1074/jbc.M601467200

    Article  CAS  PubMed  Google Scholar 

  343. Figley MD, Bieri G, Kolaitis RM, Taylor JP, Gitler AD (2014) Profilin 1 associates with stress granules and ALS-linked mutations alter stress granule dynamics. J Neurosci 34(24):8083–8097. https://doi.org/10.1523/JNEUROSCI.0543-14.2014

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  344. Stuven T, Hartmann E, Gorlich D (2003) Exportin 6: a novel nuclear export receptor that is specific for profilin–actin complexes. EMBO J 22(21):5928–5940. https://doi.org/10.1093/emboj/cdg565

    Article  PubMed  PubMed Central  Google Scholar 

  345. Bonner WM (1975) Protein migration into nuclei. I. Frog oocyte nuclei in vivo accumulate microinjected histones, allow entry to small proteins, and exclude large proteins. J Cell Biol 64(2):421–430

    Article  CAS  PubMed  Google Scholar 

  346. Feng W, Benko AL, Lee JH, Stanford DR, Hopper AK (1999) Antagonistic effects of NES and NLS motifs determine S. cerevisiae Rna1p subcellular distribution. J Cell Sci 112(Pt 3):339–347

    CAS  PubMed  Google Scholar 

  347. Plafker K, Macara IG (2000) Facilitated nucleocytoplasmic shuttling of the Ran binding protein RanBP1. Mol Cell Biol 20(10):3510–3521

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  348. Haines JD, Herbin O, de la Hera B, Vidaurre OG, Moy GA, Sun Q, Fung HY, Albrecht S, Alexandropoulos K, McCauley D, Chook YM, Kuhlmann T, Kidd GJ, Shacham S, Casaccia P (2015) Nuclear export inhibitors avert progression in preclinical models of inflammatory demyelination. Nat Neurosci 18(4):511–520. https://doi.org/10.1038/nn.3953

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  349. Kosyna FK, Depping R (2018) Controlling the gatekeeper: therapeutic targeting of nuclear transport. Cells. https://doi.org/10.3390/cells7110221

    Article  PubMed  PubMed Central  Google Scholar 

Download references

Funding

This work was in part funded by National Institutes of Health Grants GM083165, GM083165-03S1 and EY019492 to P.A.F.

Author information

Authors and Affiliations

  1. Duke University Medical Center, DUEC 3802, 2351 Erwin Road, Durham, NC, 27710, USA

    Paulo A. Ferreira

Authors
  1. Paulo A. Ferreira
    View author publications

    Search author on:PubMed Google Scholar

Corresponding author

Correspondence to Paulo A. Ferreira.

Ethics declarations

Conflict of interest

The author declares no potential conflicts of interest with respect to the research, authorship, and/or publication of this article. The author consents for the publication of this study.

Additional information

Publisher's Note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Ferreira, P.A. The coming-of-age of nucleocytoplasmic transport in motor neuron disease and neurodegeneration. Cell. Mol. Life Sci. 76, 2247–2273 (2019). https://doi.org/10.1007/s00018-019-03029-0

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue date:

  • DOI: https://doi.org/10.1007/s00018-019-03029-0

Keywords