The tumour suppressor CYLD is a negative regulator of RIG-I-mediated antiviral response
The tumour suppressor CYLD is a negative regulator of RIG-I-mediated antiviral response
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DOI：
10.1038/embor.2008.136
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发表时间：
2008-09-01
期刊：
影响因子：
7.7
通讯作者：
Ting, Adrian T.
中科院分区：
文献类型：
--
作者：
Friedman, Constantin S.;O'Donnell, Marie Anne;Ting, Adrian T.
在检测到病毒RNA时，RNA解旋酶视黄酸诱导基因I（RIG - I）激活干扰素调节因子3（IRF3）信号通路，以诱导I型干扰素（IFN）基因转录。对于这种抗病毒信号通路如何可能受到负调控，人们知之甚少。基因芯片和生物信息学分析表明，RIG - I的表达与肿瘤抑制因子CYLD（圆柱瘤病）的表达密切相关，CYLD是一种去泛素化酶，可去除赖氨酸63连接的多聚泛素链，这提示这两种分子之间存在功能关联。CYLD的异位表达抑制由RIG - I触发的IRF3信号通路和干扰素产生；相反，CYLD的敲低增强这种反应。CYLD从RIG - I以及从TANK结合激酶1（TBK1）（使IRF3磷酸化的激酶）上移除多聚泛素链，这与IRF3信号通路的抑制同时发生。此外，在肿瘤坏死因子和病毒感染存在的情况下，CYLD蛋白水平降低，同时干扰素产生增强。这些发现表明CYLD是RIG - I介导的天然抗病毒反应的负调控因子。
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.