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Review
. 2012 Nov;12(11):774-85.
doi: 10.1038/nri3313. Epub 2012 Oct 12.

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

Averil Ma  1 , Barbara A Malynn
Affiliations
Review

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

Averil Ma et al. Nat Rev Immunol. 2012 Nov.

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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Figures

Figure 1
Figure 1. Polymorphisms or mutations in TNFAIP3 and human diseases
The figure shows a schematic of the TNFAIP3 gene locus, which encodes A20. Exons encoding the amino-terminal OTU domain are shown in orange and exons encoding the carboxy-terminal zinc fingers (ZFs) of A20 are shown in green. The C103, ZF4 and ZF7 motifs are highlighted. Non-coding exons, including AT-rich sequences at the end of exon 9, are shown in brown. Human germline single-nucleotide polymorphisms (SNPs) in the TNFAIP3 locus that are associated with autoimmune and autoinflammatory diseases are indicated (labelled with their reference SNP (rs) numbers)–, as are somatic mutations that have been identified in the coding exons of TNFAIP3 in human B cell lymphomas–.
Figure 2
Figure 2. Biochemical characteristics of A20 protein function
The de-ubiquitylating (DUB) activity of A20 is mediated by the catalytic cysteine at position 103 (C103) within the OTU domain. A20 also contains seven zinc fingers (ZFs), which mediate its E3 ubiquitin ligase activity (via ZF4) and its ubiquitin-binding activity. Indeed, A20 binds to ubiquitylated E2 enzymes such as UBCH5A via ZF4–ZF7, to K63-linked polyubiquitin chains via ZF4 (REF. 23) and to linear polyubiquitin chains via ZF7 (REFS 24,90,91). A20 also interacts with substrates such as receptor-interacting protein 1 (RIP1) via ZF1–ZF3 (with ZF1 being crucial for binding),, with E3 enzymes such as TNFR-associated factor 6 (TRAF6) via the OTU domain, and with ubiquitin-binding proteins such as TAX1-binding protein 1 (TAX1BP1), IκB kinase-γ (IKKγ), A20-binding inhibitor of NF-κB activation 1 (ABIN1) and ABIN2 via the ZF domain. Some of these latter interactions may occur through the mutual binding of A20 and the interacting protein to ubiquitin chains. The regions that mediate the interaction of A20 with the E3 enzymes RING-finger protein 11 (RNF11) and ITCH, as well as with itself, have not been clearly defined. In addition to their other functions, the C103 and ZF4 motifs have been shown to support the degradation of E2 enzymes. A20 also undergoes post-translational modifications; for example, a site of A20 phosphorylation by IKKβ is indicated. Human A20 is cleaved by the paracaspase MALT1 at the site indicated by an asterisk. The site at which mouse A20 is cleaved has not been precisely determined, but the region where it is cleaved is indicated by a bracket.
Figure 3
Figure 3. A20-dependent regulation of ubiquitin-dependent signalling pathways
A20 regulates multiple ubiquitin-dependent innate immune signalling cascades, including those downstream of tumour necrosis factor receptor 1 (TNFR1), interleukin-1 receptor (IL-1R), Toll-like receptor 4 (TLR4) and nucleotide-binding oligomerization domain (NOD) proteins. During these signalling cascades, E2 enzymes, such as UBCH5 and UBC13, and E3 ligases, such as cellular inhibitor of apoptosis (cIAP) proteins, TNFR-associated factor 6 (TRAF6), and perhaps TRAF2, collaborate to build polyubiquitin chains. These polyubiquitin chains can be K48-linked, K63-linked or joined by other linkages, and are attached to substrates such as receptor-interacting protein 1 (RIP1), TRAF6, IκB kinase-γ (IKKγ) and RIP2. A distinct enzymatic complex known as LUBAC (linear ubiquitin chain assembly complex) builds linear polyubiquitin chains on RIP1 and IKKγ, . In addition, unanchored ubiquitin chains (that is, chains that are not covalently attached to signalling proteins) are integral to these cascades. A20 may regulate these signalling complexes by cleaving K63-linked ubiquitin chains from RIP1, TRAF6 and/or IKKγ through the de-ubiquitylating (DUB) activity of its OTU domain. A20 can also regulate these signalling pathways by supporting the degradation of the E2 enzymes UBCH5 and UBC13, thereby inhibiting E3 ligase activity that is dependent on these E2 enzymes. Finally, A20 can build K48-linked polyubiquitin chains on RIP1, which leads to its degradation. In addition, the ZF4 and ZF7 domains of A20 have been shown in vitro to bind to K63-linked ubiquitin chains and linear ubiquitin chains, respectively, on IKK complexes and TNFR complexes and may use these interactions to facilitate the inhibition of these signalling complexes. Although it is not shown in the figure, the ubiquitin-binding activities of A20 might also compete with those of other ubiquitin-binding proteins and/or help A20 to function as an adaptor protein for other regulators, such as A20-binding inhibitor of NF-κB activation 1 (ABIN1), ITCH, RING-finger protein 11 (RNF11) or TAX1-binding protein 1 (TAX1BP1). In addition to restricting TNFR, IL-1R, TLR and NOD signals, A20 regulates signals triggered by the T cell receptor (not shown) and CD40 (not shown). Finally, A20 restricts TNF-induced apoptosis, possibly by restricting the ubiquitylation of caspase 8 (REFS 14,88) (not shown). IRAK, IL-1R-associated kinase; LPS, lipopolysaccharide; MDP, muramyl dipeptide; NF-κB, nuclear factor-κB; TAB, TAK1-binding protein; TAK1, TGFβ-activated kinase 1; TRADD, TNFR1-associated death domain protein; ZF, zinc finger.
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References

    1. Baltimore D. NF-κB is 25. Nature Immunol. 2011;12:683–685. - PubMed
    1. Rui L, Schmitz R, Ceribelli M, Staudt LM. Malignant pirates of the immune system. Nature Immunol. 2011;12:933–940. - PubMed
    1. Greten FR, et al. IKKβ links inflammation and tumorigenesis in a mouse model of colitis-associated cancer. Cell. 2004;118:285–296. - PubMed
    1. Pickart CM, Eddins MJ. Ubiquitin: structures, functions, mechanisms. Biochim. Biophys. Acta. 2004;1695:55–72. - PubMed
    1. Chen ZJ. Ubiquitination in signaling to and activation of IKK. Immunol. Rev. 2012;246:95–106. - PMC - PubMed

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