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Review
. 2012 Mar;246(1):107-24.
doi: 10.1111/j.1600-065X.2012.01100.x.

Regulation of NF-κB by deubiquitinases

Edward W Harhaj  1 , Vishva M Dixit
Affiliations
Review

Regulation of NF-κB by deubiquitinases

Edward W Harhaj et al. Immunol Rev. 2012 Mar.

Abstract

The nuclear factor-κB (NF-κB) pathway is a critical regulator of innate and adaptive immunity. Noncanonical K63-linked polyubiquitination plays a key regulatory role in NF-κB signaling pathways by functioning as a scaffold to recruit kinase complexes containing ubiquitin-binding domains. Ubiquitination is balanced by deubiquitinases that cleave polyubiquitin chains and oppose the function of E3 ubiquitin ligases. Deubiquitinases therefore play an important role in the termination of NF-κB signaling and the resolution of inflammation. In this review, we focus on NF-κB regulation by deubiquitinases with an emphasis on A20 and CYLD. Deubiquitinases and the ubiquitin/proteasome components that regulate NF-κB may serve as novel therapeutic targets for inflammatory diseases and cancer.

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Conflict of interest statement

The authors declare no conflicts of interest.

Figures

Fig. 1
Fig. 1. Mechanisms of A20 inhibition of NF-κB
(A) The ubiquitin-editing function of A20. In response to TNF stimulation, A20 expression is induced and inhibits NF-κB in a negative feedback loop in a two-step manner. (1) A20 first hydrolyzes K63-linked polyubiquitin chains on RIP1 in an OTU-dependent manner to inhibit IKK and NF-κB signaling. (2) A20 then conjugates K48-linked polyubiquitin chains onto RIP1 to trigger its proteasomal degradation. (B) Disruption of E2:E3 ubiquitin enzyme complexes by A20. The E3 ligase TRAF6 inducibly interacts with the E2 enzymes Ubc13 and UbcH5c upon IL-1R/TLR4 stimulation. (1) A20 interacts with Ubc13, UbcH5c and TRAF6 and disrupts the binding between TRAF6 and the E2 enzymes. (2) A20 then conjugates K48-linked polyubiquitin chains on Ubc13 (and UbcH5c) to trigger its proteasomal degradation.
Fig. 2
Fig. 2. Signaling pathways regulated by A20, CYLD, and other DUBs
(A) TNF binding to TNFR1 triggers the K63-linked polyubiquitination of RIP1 which is negatively regulated by A20, CYLD and possibly other DUBs (Cezanne, USP21, etc.). (B) IL-1 binding to the IL-1R or LPS binding to TLR4 triggers the activation and K63-linked polyubiquitination of TRAF6 which is negatively regulated by A20, CYLD and USP7. (C) Sensing of MDP by NOD2 facilitates the K63-linked polyubiquitination of RIP2 which is counteracted by A20. (D) T-cell receptor engagement by antigen and costimulation activates PKCθ and the CBM complex leading to MALT1 K63-linked polyubiquitination. A20 inhibits MALT1 ubiquitination, however MALT1 cleaves A20 to inactivate its function. CYLD also hydrolyzes K63-linked polyubiquitin chains from TAK1 in peripheral T cells. (E) RIG-I/MDA5 sense viral nucleic acid and inducibly interact with the mitochondrial adaptor molecule MAVS which assembles a signaling complex containing the E3 ligase TRAF3 and the kinases TBK1/IKKi. CYLD inhibits antiviral signaling by removing K63-linked polyubiquitin chains from RIG-I. DUBA removes K63-linked polyubiquitin chains from TRAF3. A20, together with ABIN1 and TAX1BP1, remove K63-linked polyubiquitin chains from TBK1/IKKi. (F) RANK ligand/RANK ligation in osteoclasts triggers TRAF6 activation and polyubiquitination. CYLD cleaves K63-linked polyubiquitin chains from TRAF6 and requires the adaptor molecule p62 to interact with TRAF6.
Fig. 3
Fig. 3. Activation and assembly of the A20 ubiquitin-editing complex
TNF stimulation activates NF-κB and induces A20 expression as part of a negative feedback loop. IKKα phosphorylates TAX1BP1 on Ser593 and Ser624 which nucleates the A20 ubiquitin-editing complex and is required 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.
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