The tumour suppressor CYLD is a negative regulator of RIG‐I‐mediated antiviral response

Abstract

On detecting viral RNAs, the RNA helicase retinoic acid-inducible gene I (RIG-I) activates the interferon regulatory factor 3 (IRF3) signalling pathway to induce type I interferon (IFN) gene transcription. How this antiviral signalling pathway might be negatively regulated is poorly understood. Microarray and bioinformatic analysis indicated that the expression of RIG-I and that of the tumour suppressor CYLD (cylindromatosis), a deubiquitinating enzyme that removes Lys 63-linked polyubiquitin chains, are closely correlated, suggesting a functional association between the two molecules. Ectopic expression of CYLD inhibits the IRF3 signalling pathway and IFN production triggered by RIG-I; conversely, CYLD knockdown enhances the response. CYLD removes polyubiquitin chains from RIG-I as well as from TANK binding kinase 1 (TBK1), the kinase that phosphorylates IRF3, coincident with an inhibition of the IRF3 signalling pathway. Furthermore, CYLD protein level is reduced in the presence of tumour necrosis factor and viral infection, concomitant with enhanced IFN production. These findings show that CYLD is a negative regulator of RIG-I-mediated innate antiviral response. Keywords: cylindromatosis; interferon; IRF3; RIG-I; ubiquitin EMBO reports (2008) 9, 930-936.

FLN29 Deficiency Reveals Its Negative Regulatory Role in the Toll-like Receptor (TLR) and Retinoic Acid-inducible Gene I (RIG-I)-like Helicase Signaling Pathway

“…5, D and E), it is likely that FLN29 might target the multiprotein complex composed of these molecules. Recent studies have identified negative regulatory proteins such as A20, CYLD, and DUBA, all of which possess deubiquitination activity (DUB) toward several signaling molecules, including RIG-I, TRAF3, and TRAF6 (17)(18)(19)(20)(21). FLN29 protein, however, does not contain a DUB domain and therefore is unlikely to function as a DUB.…”

“…SOCS1, IRAK-M, and A20 have been identified as such negative regulators of the TLR-NF-B pathway (12)(13)(14). Additionally, DUBA, RNF125, SHP-2, Cyld, and A20 have been reported as negative regulators of the RLH-IRF3 pathway (15)(16)(17)(18)(19)(20)(21). In our previous study, we demonstrated that FLN29 protein induced by type I or II IFNs acts as a negative regulator for the TLR4-TRAF6 signaling pathway in macrophages.…”

Regulation of Virus-triggered Signaling by OTUB1- and OTUB2-mediated Deubiquitination of TRAF3 and TRAF6

“…In contrast, the E3 ubiquitin ligase RNF125 catalyzes Lys 48 -linked ubiquitination of RIG-I and negatively regulates RIG-I-mediated signaling (24). In addition, an OTU (ovarian tumor domain) containing deubiquitinating enzyme, CYLD, dissociates Lys 63 -linked ubiquitin moieties from RIG-I, and therefore negatively regulates RIG-Imediated signaling (25,26). The ubiquitination/deubiquitination systems also target other components in the virus-triggered pathways.…”

Negative Regulation of Melanoma Differentiation-associated Gene 5 (MDA5)-dependent Antiviral Innate Immune Responses by Arf-like Protein 5B

“…RNF125 inhibits RIG-I signaling by K48 polyubiquitination and proteasome-mediated degradation of RIG-I (24). CYLD and USP4 are deubiquitinases that remove K63-or K48-linked polyubiquitin chains, respectively, from RIG-I to inhibit RIG-I signaling (25,26). Collectively, there are multiple mechanisms that negatively regulate RLR-mediated antiviral responses.…”