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A20: linking a complex regulator of ubiquitylation to immunity and human disease

Key Points

  • Polymorphisms of the gene encoding A20 confer susceptibility to multiple autoimmune and inflammatory diseases, including systemic lupus erythematosus, rheumatoid arthritis, psoriasis, coeliac disease, inflammatory bowel disease, type 2 diabetes and atherosclerosis.

  • A20 is a tumour suppressor for human lymphomas, as biallelic somatic mutations that inactivate A20 occur at a high frequency in human B cell lymphomas.

  • A20-deficient mice die perinatally owing to multiorgan inflammation. Lineage-specific deletions of the gene encoding A20 have shown that A20 performs a variety of cell type-specific functions that prevent autoimmunity and autoinflammatory diseases.

  • A20 regulates multiple ubiquitin-dependent cellular activation and survival signals downstream of tumour necrosis factor receptors, Toll-like receptors, the interleukin-1 receptor, NOD-like receptors, CD40 and antigen receptors.

  • A20 is a multifunctional protein that binds to K63-linked and linear polyubiquitin chains and exhibits both de-ubiquitylation and E3 ubiquitin ligase activities. How these activities are coordinated, and how they are utilized in distinct signalling complexes, is currently unclear.

  • A20 cooperates with other ubiquitin-binding and ubiquitin-modifying proteins to form larger ubiquitin-editing complexes that may provide higher degrees of specificity and regulation of ubiquitin-dependent signalling.

  • The extensive associations of A20 and its associated proteins with human diseases suggest that modification of the expression or functions of A20 may provide potent therapeutic opportunities.

Abstract

A20 (also known as TNFAIP3) is a potent anti-inflammatory signalling molecule that restricts multiple intracellular signalling cascades. Recent studies in three general areas have converged to highlight the clinical and biological importance of A20. First, human genetic studies have strongly linked polymorphisms and mutations in the gene encoding A20 to inflammatory, autoimmune and malignant diseases. Second, studies in gene-targeted mice have revealed that A20 regulates multiple immune cell functions and prevents experimental diseases that closely mimic human conditions. Third, biochemical studies have unveiled complex mechanisms by which A20 regulates ubiquitin-dependent nuclear factor-κB and cell-survival signals. Taken together, these studies are revealing the importance of A20-mediated regulation of ubiquitin-dependent signalling in human disease.

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Figure 1: Polymorphisms or mutations in TNFAIP3 and human diseases.
Figure 2: Biochemical characteristics of A20 protein function.
Figure 3: A20-dependent regulation of ubiquitin-dependent signalling pathways.

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Acknowledgements

Work from the authors' laboratory was supported by the US National Institutes of Health.

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Glossary

Ubiquitylation

The covalent attachment of single ubiquitin molecules or ubiquitin chains to proteins to regulate their interactions with proteasomal components and other proteins. Protein ubiquitylation occurs in three enzymatic steps that require a ubiquitin-activating enzyme (E1), a ubiquitin-conjugating enzyme (E2) and a ubiquitin ligase (E3), respectively. The ligase catalyses the formation of an isopeptide bond between the carboxyl terminus of ubiquitin and an amino group belonging to a lysine residue of the target protein.

Single-nucleotide polymorphisms

(SNPs). Variations in DNA sequence in which one of the four nucleotides is substituted for another (for example, C for A). SNPs are the most frequent type of polymorphism in the genome.

Apoptosis

A common form of cell death. Many physiological and developmental stimuli cause apoptosis, and this mechanism is frequently used to delete unwanted, superfluous or potentially harmful cells, such as those undergoing transformation.

Activation-induced cytidine deaminase

(AID). An enzyme that is required for two crucial events in the germinal centre: somatic hypermutation and class-switch recombination.

Dextran sulphate sodium (DSS)-induced colitis

A commonly used experimental model of colitis induced in mice by ingestion of the sulphated polysaccharide DSS. This model causes acute colonic epithelial damage and inflammation via unknown mechanisms.

Tight junctions

A belt-like region of adhesion between adjacent epithelial or endothelial cells that regulates paracellular flux. Tight-junction proteins include the integral membrane proteins occludin and claudin, in association with cytoplasmic zonula occludens proteins.

Ectodysplasin A receptor

(EDAR). A member of the TNFR family that can activate NF-κB-, JNK- and caspase-independent cell signalling pathways. EDAR pathways are important for the development of ectodermal structures, such as hair follicles, sweat glands and teeth.

Cellular inhibitor of apoptosis

A family of proteins (comprising cIAP1, cIAP2, XIAP and NAIP) that contain a BIR domain and that can act as E3 ubiquitin ligases and as inhibitors of caspases.

MicroRNAs

Endogenous single-stranded RNA molecules of approximately 21–23 nucleotides in length that regulate the expression of other genes by binding to mRNAs and inducing RNA degradation.

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Ma, A., Malynn, B. A20: linking a complex regulator of ubiquitylation to immunity and human disease. Nat Rev Immunol 12, 774–785 (2012). https://doi.org/10.1038/nri3313

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