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Review
. 2012 Mar;9(2):123-30.
doi: 10.1038/cmi.2011.59. Epub 2012 Feb 20.

Regulation of NF-κB signaling by the A20 deubiquitinase

Noula Shembade  1 , Edward W Harhaj
Affiliations
Review

Regulation of NF-κB signaling by the A20 deubiquitinase

Noula Shembade et al. Cell Mol Immunol. 2012 Mar.

Abstract

The NF-κB transcription factor is a central mediator of inflammatory and innate immune signaling pathways. Activation of NF-κB is achieved by K63-linked polyubiquitination of key signaling molecules which recruit kinase complexes that in turn activate the IκB kinase (IKK). Ubiquitination is a highly dynamic process and is balanced by deubiquitinases that cleave polyubiquitin chains and terminate downstream signaling events. The A20 deubiquitinase is a critical negative regulator of NF-κB and inflammation, since A20-deficient mice develop uncontrolled and spontaneous multi-organ inflammation. Furthermore, specific polymorphisms in the A20 genomic locus predispose humans to autoimmune disease. Recent studies also indicate that A20 is an important tumor suppressor that is inactivated in B-cell lymphomas. Therefore, targeting A20 may form the basis of novel therapies for autoimmune disease and lymphomas.

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Figures

Figure 1
Figure 1
Mechanisms of NF-κB inhibition by A20 in the TNFR1 signaling pathway. A20 is induced by NF-κB in the TNFR1 pathway and functions in a negative feedback loop. The A20 adaptor molecule TAX1BP1 is phosphorylated on Ser593 and Ser624 by IKKα which nucleates the A20 ubiquitin-editing complex and is essential for interactions between TAX1BP1, Itch, RNF11 and A20. The A20 ubiquitin-editing complex inhibits RIP1 K63-linked polyubiquitination to terminate NF-κB signaling downstream of TNFR1. IKK, IκB kinase; RNF11, ring finger protein 11; TAX1BP1, Tax1-binding protein 1; TNFR1, TNF receptor 1.
Figure 2
Figure 2
Mechanisms of NF-κB inhibition by A20 in IL-1R/TLR4 signaling pathways. A20 is induced by NF-κB downstream of IL-1R/TLR4. TAX1BP1 cooperates with A20 to disrupt the interactions between the E3 ligase TRAF6 and the E2 enzymes Ubc13 and UbcH5c upon IL-1R/TLR4 stimulation. At later times, A20 conjugates K48-linked polyubiquitin chains on the E2 enzymes to trigger their proteasomal degradation. TAX1BP1, Tax1-binding protein 1.
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References

    1. Hayden MS, Ghosh S. Shared principles in NF-κB signaling. Cell. 2008;132:344–362. - PubMed
    1. Hayden MS, Ghosh S. Signaling to NF-κB. Genes Dev. 2004;18:2195–2224. - PubMed
    1. Hacker H, Karin M. Regulation and function of IKK and IKK-related kinases. Sci STKE. 2006;2006:re13. - PubMed
    1. Sun SC, Ganchi PA, Ballard DW, Greene WC. NF-κB controls expression of inhibitor IκBα: evidence for an inducible autoregulatory pathway. Science. 1993;259:1912–1915. - PubMed
    1. Hershko A, Ciechanover A. The ubiquitin system. Annu Rev Biochem. 1998;67:425–479. - PubMed

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