Direct, Noncatalytic Mechanism of IKK Inhibition by A20

Skaug, Brian; Chen, Jueqi; Du, Fenghe; He, Jin; Ma, Averil; Chen, Zhijian J.

doi:10.1016/j.molcel.2011.09.015

Cited by 223 publications

(211 citation statements)

References 42 publications

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“…Although p47 and these DUBs recognize polyubiquitin chains that are generated for NF-κB activation, p47 negatively regulates IKK activation in a manner that is mechanistically distinct from that of A20 and CYLD. It has been proposed that A20 regulates both the initial and termination phases of stimulation-induced NF-κB activation [57][58][59] , whereas CYLD is involved in blocking spontaneous NF-κB activation as well as in the initial phase 25,60 . Given that p47 and these DUBs negatively regulate the initial phase of stimulation-induced NF-κB activation and that CYLD inhibits the interaction of p47 with NEMO, p47 and these two DUBs could cooperatively regulate the initial phase of stimulation-induced NF-κB activation for achieving the appropriate expression levels of NF-κB target genes.…”

Section: Discussionmentioning

confidence: 99%

p47 negatively regulates IKK activation by inducing the lysosomal degradation of polyubiquitinated NEMO

et al. 2012

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The persistent or excess activation of nF-κB causes various inflammatory and autoimmune diseases, but the molecular mechanisms that negatively regulate nF-κB activation are not fully understood. Here we show that p47, an essential factor for Golgi membrane fusion, associates with the nEmo subunit of the IκB kinase (IKK) complex upon TnF-α or IL-1 stimulation, and inhibits IKK activation. p47 binds to Lys63-linked and linear polyubiquitin chains, which are conjugated to nEmo upon such stimulation. The binding of p47 to polyubiquitinated nEmo triggers the lysosomal degradation of nEmo, thereby inhibiting IKK activation. The silencing of p47 results in enhanced TnF-α-or IL-1-induced IKK activation, and an increased expression of genes encoding inflammatory mediators. Taken together, our results suggest that p47 is critical for negatively regulating stimulation-induced IKK activation in a manner that is mechanistically distinct from the previously characterized negative regulators, such as A20 and CYLD.

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Section: Discussionmentioning

confidence: 99%

p47 negatively regulates IKK activation by inducing the lysosomal degradation of polyubiquitinated NEMO

et al. 2012

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“…In contrast, A20 does not act as a processive DUB for K63-linked polyubiquitin chains but (39) effectively cleaves entire K63-linked polyubiquitin chains from substrates such as TRAF6, thereby demonstrating specificity for particular polyubiquitinated substrates (40). In addition, A20 can limit NF-kB activation through noncatalytic mechanisms including lysosomal targeting of TRAF2 (41) and direct IkB kinase inhibition (42). In vivo, A20 is involved both in the addition of K48-linked polyubiquitin chains to induce the proteasomal degradation of various target proteins (43,44) and the removal of K63-linked ubiquitin chains to terminate signaling (8,43,45,46).…”

Section: Discussionmentioning

confidence: 99%

A20 and CYLD Do Not Share Significant Overlapping Functions during B Cell Development and Activation

Chu

Soberon

Glockner

et al. 2012

The Journal of Immunology

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The ubiquitin-editing enzyme A20 (TNFAIP3) and the deubiquitinase CYLD are central negative regulators of NF-kappa B signaling. Both can act by removing nonproteolytic K63-linked polyubiquitin chains from an overlapping set of signaling molecules. In B cells, A20 deficiency results in hyperactivity, loss of immune homeostasis, inflammation, and autoimmunity. The reported consequences of CYLD deficiency are controversial, ranging from an absence of effects to dramatic B cell hyperplasia. These differences could be due to varying compensation for the loss of CYLD function by A20. Therefore, to explore potential overlapping physiological functions between A20 and CYLD, we generated and characterized A20/CYLD double-deficient B cells. Interestingly, the lack of both A20 and CYLD did not exacerbate the developmental defects and hyperresponsive activity of A20-deficient B cells. In addition, the extent of B cell activation after in vitro stimulation with anti-CD40, LPS, and CpG was comparable in B cells lacking A20/CYLD and A20 alone. However, in response to BCR cross-linking, we observed small but reproducible additive effects of the lack of A20 and CYLD. Taken together, our results demonstrate that A20 and CYLD do not share significant functions during B cell development and activation. The Journal of Immunology, 2012, 189: 4437-4443

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“…It can also antagonize interactions between various other E3 enzymes with the E2 enzymes UBC13 and UbcH5c (237). Furthermore, ubiquitin chain binding by intrinsic A20 ZnF domains influence ubiquitin dynamics on the NF B pathway (23,239). In vitro data indicate DUB specificity for Lys48-over Lys63-linked chains, but cellular models suggest a critical role in cleaving activating Lys63 chains en bloc from mediators of NF B signaling, such as receptor interacting protein 1 (RIP1) (123,156,271).…”

Section: Otu Familymentioning

confidence: 99%

Deubiquitylases From Genes to Organism

Clague

Barsukov

Coulson

et al. 2013

Physiological Reviews

376

384

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Ubiquitylation is a major posttranslational modification that controls most complex aspects of cell physiology. It is reversed through the action of a large family of deubiquitylating enzymes (DUBs) that are emerging as attractive therapeutic targets for a number of disease conditions. Here, we provide a comprehensive analysis of the complement of human DUBs, indicating structural motifs, typical cellular copy numbers, and tissue expression profiles. We discuss the means by which specificity is achieved and how DUB activity may be regulated. Generically DUB catalytic activity may be used to 1) maintain free ubiquitin levels, 2) rescue proteins from ubiquitin-mediated degradation, and 3) control the dynamics of ubiquitin-mediated signaling events. Functional roles of individual DUBs from each of five subfamilies in specific cellular processes are highlighted with an emphasis on those linked to pathological conditions where the association is supported by whole organism models. We then specifically consider the role of DUBs associated with protein degradative machineries and the influence of specific DUBs upon expression of receptors and channels at the plasma membrane.

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Direct, Noncatalytic Mechanism of IKK Inhibition by A20

Cited by 223 publications

References 42 publications

p47 negatively regulates IKK activation by inducing the lysosomal degradation of polyubiquitinated NEMO

p47 negatively regulates IKK activation by inducing the lysosomal degradation of polyubiquitinated NEMO

A20 and CYLD Do Not Share Significant Overlapping Functions during B Cell Development and Activation

Deubiquitylases From Genes to Organism

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