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Review
. 2010 Jan;17(1):25-34.
doi: 10.1038/cdd.2009.43.

V体育ios版 - CYLD: a tumor suppressor deubiquitinase regulating NF-kappaB activation and diverse biological processes

S-C Sun  1
Affiliations
Review

V体育官网 - CYLD: a tumor suppressor deubiquitinase regulating NF-kappaB activation and diverse biological processes

S-C Sun (VSports注册入口). Cell Death Differ. 2010 Jan.

Abstract (V体育ios版)

Protein ubiquitination is a reversible reaction, in which the ubiquitin chains are deconjugated by a family of deubiquitinases (DUBs). The presence of a large number of DUBs suggests that they likely possess certain levels of substrate selectivity and functional specificity. Indeed, recent studies show that a tumor suppressor DUB, cylindromatosis (CYLD), has a predominant role in the regulation of NF-kappaB, a transcription factor that promotes cell survival and oncogenesis. NF-kappaB activation involves attachment of K63-linked ubiquitin chains to its upstream signaling factors, which is thought to facilitate protein-protein interactions in the assembly of signaling complexes. By deconjugating these K63-linked ubiquitin chains, CYLD negatively regulates NF-kappaB activation, which may contribute to its tumor suppressor function. CYLD also regulates diverse physiological processes, ranging from immune response and inflammation to cell cycle progression, spermatogenesis, and osteoclastogenesis. Interestingly, CYLD itself is subject to different mechanisms of regulation VSports手机版. .

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Figures

Figure 1
Figure 1
Regulation of canonical and noncanonical pathways of NF-κB activation by cylindromatosis (CYLD). NF-κB can be activated by canonical and noncanonical pathways, which rely on IκB degradation and p100 processing, respectively. Noncanonical NF-κB signaling involves receptor-mediated degradation of negative regulatory ubiquitin ligase complex, c-IAP/TRAF2/TRAF3, and accumulation of NIK. The canonical pathway involves K63 type of ubiquitination of several signaling components, particularly receptor-interacting protein 1 (RIP1), which is required for the recruitment and activation of IκB kinase (IKK) and its activating kinase, Tak1. This pathway can be stimulated by various immune receptors, including TNFR1 (shown in the figure), IL-1R, TLRs, antigen receptors, etc (not shown). Activation of IKK by TNFR1 involves RIP1 ubiquitination by the E3 ubiquitin ligases, TRAF2, and cIAP1 and 2 (cIAP1/2)., Additionally, K63-linked ubiquitination of an NF-κB coactivator, Bcl3, promotes its nuclear translocation and, thereby, enhances NF-κB function. The different NF-κB complexes regulate distinct target genes, although they may function cooperatively in many cases. CYLD deubiquitinates the canonical NF-κB signaling components and Bcl3, and negatively regulates the NF-κB activation and Bcl3 nuclear translocation. Additionally, CYLD may also indirectly inhibit the atypical NF-κB pathways, as the inducible expression of noncanonical NF-κB members, RelB and NF-κB2 p100, and the coactivator, Bcl3, depends on the canonical NF-κB activation
Figure 2
Figure 2
Two mechanisms of apoptosis induction by cylindromatosis (CYLD). Stimulation of TNFR1 triggers lysine 63 (K63)-linked ubiquitination of receptor-interacting protein 1 (RIP1), which in turn leads to activation of the survival factor NF-κB. Deubiquitination of RIP1 by CYLD not only inhibits activation of the survival factor, NF-κB, but also promotes the engagement and activation of caspase 8 by RIP1. A20, a molecule with K63-specific DUB activity and K48-specific E3 ligase activity, mediates ubiquitin chain editing and converts the ubiquitin chains of RIP1 to the proteosome-targeting K48 type
Figure 3
Figure 3
Structural domains of cylindromatosis (CYLD). The C-terminal portion of CYLD contains a ubiquitin-specific protease (USP) catalytic domain, with an inserted a zinc-binding B-box domain. The N-terminal portion of CYLD has three CAP-Gly domains (CAP), the third of which forms the NF-κB essential modulator (NEMO)-binding domain, and two proline-rich (PR) motifs. CYLD also contains a TRAF-binding motif (PVQES) and a phosphorylation (P) region. The C-terminal portion of CYLD (amino acids 470–957) is known to bind Bcl-3, although the precise Bcl-3-binding domain has not been defined
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