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Review
. 2013 Feb;25(1):4-12.
doi: 10.1016/j.coi.2012.12.005. Epub 2013 Jan 8.

Regulation of NF-κB by ubiquitination

Jueqi Chen  1 , Zhijian J Chen
Affiliations
Review

Regulation of NF-κB by ubiquitination

Jueqi Chen et al. Curr Opin Immunol. 2013 Feb.

Abstract

The nuclear factor κ enhancer binding protein (NF-κB) family of transcription factors regulates the expression of a large array of genes involved in diverse cellular processes including inflammation, immunity and cell survival. Activation of NF-κB requires ubiquitination, a highly conserved and versatile modification that can regulate cell signaling through both proteasome dependent and independent mechanisms. Studies in the past few years have provided new insights into the mechanisms underlying regulation of NF-κB by ubiquitination, including the involvement of multiple linkages of ubiquitin, the essential role of ubiquitin binding, and the function of unanchored polyubiquitin chains. In this review, we will focus on recent advances in understanding the role of ubiquitination in NF-κB regulation in various pathways.

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Figures

Figure 1
Figure 1. NF-κB activation by inflammatory cytokines
Stimulation of cells with IL-1β leads to the activation of the ubiquitin E3 ligase TRAF6, which catalyzes the synthesis of unanchored K63 polyubiquitin chains that bind to the TAB2 subunit of the TAK1 kinase complex, resulting in TAK1 activation. TAK1 then phosphorylates IKKβ, leading to NF-κB activation. In the TNFα pathway, stimulation of the cells leads to the recruitment of several ubiquitin E3 ligases to the receptor, including TRAF2, TRAF5, cIAP1, cIAP2 and LUBAC (consisting of HOIP, HOIL-1, and Sharpin). These E3s and Ubch5 synthesize ubiquitin chains of different linkages, including K63, K11 and linear (M1). The physiological targets of these ubiquitin chains are still not clear, but it is clear that the ubiquitination events lead to TAK1 and IKK activation. Two bacterial proteins, OspI and NleE, are able to inhibit NF-κB activation by targeting Ubc13 and TAB2/3, respectively.
Figure 2
Figure 2. The role of ubiquitination in the RIG-I antiviral signaling pathway
After infection by RNA viruses, viral RNA binds to RIG-I and induces a conformational change that exposes the N-terminus of RIG-I which binds to unanchored K63 polyubiquitin chains synthesized by TRIM25 and Riplet. RIG-I then interacts with and activates the mitochondrial membrane protein MAVS, which activates IKK and TBK1 in the cytoplasm. These kinases then activate NF-κB and IRF3, leading to the production of type-I interferons.
Figure 3
Figure 3. Mechanisms of IKK inhibition by A20
A20 inhibits IKK through three proposed mechanisms. (A) A20 functions as an editing enzyme that first utilizes the N-terminal OTU-type deubiquitination enzyme domain to remove K63 polyubiquitin chains from RIP1, followed by K48 polyubiquitination of RIP1 by the C-terminal zinc finger (ZnF4) domain, which functions as a ubiquitin E3 ligase. K48 polyubiquitination of RIP1 targets it for degradation by the proteasome. (B) A20 can inhibit the synthesis of polyubiquitin chains by disrupting the interaction between E2s (Ubc13 and Ubc5) and E3s (TRAFs and cIAPs). (C) A20 can also inhibit IKK through a non-catalytic mechanism that involves its binding to K63 and linear polyubiquitin chains through the zinc finger 7 (ZnF7) domain. This binding facilitates the formation of a complex consisting of A20, NEMO and polyubiquitin chains, resulting in inhibition of IKK phosphorylation by TAK1. A20 also forms a complex with RNF11, ITCH and TAX1BP1, which regulate the inhibitory activity of A20. TAX1BP1 is phosphorylated by IKKα, and this phosphorylation promotes the assembly of the A20 complex to provide a negative feedback inhibition of IKK.
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