WDR82 Negatively Regulates Cellular Antiviral Response by Mediating TRAF3 Polyubiquitination in Multiple Cell Lines
WDR82 Negatively Regulates Cellular Antiviral Response by Mediating TRAF3 Polyubiquitination in Multiple Cell Lines
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DOI：
10.4049/jimmunol.1500339
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发表时间：
2015-10
期刊：
影响因子：
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通讯作者：
Kun Zhu;Xiang Wang;Lin-Gao Ju;Yuan Zhu;Jie Yao;Yanyi Wang;Min Wu;Lian-Yun Li
中科院分区：
文献类型：
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作者：
Kun Zhu;Xiang Wang;Lin-Gao Ju;Yuan Zhu;Jie Yao;Yanyi Wang;Min Wu;Lian-Yun Li
病毒感染后，宿主细胞中的视黄酸诱导基因I样受体识别病毒RNA并激活I型IFN表达。以前，我们确定WD重复结构域（WDR）5作为一个积极的调节通路激活。在这项研究中，我们报告说，WDR 82，WDR 5的同源蛋白，WDR 5相反，并抑制视黄酸诱导的基因I信号通路的激活。WDR 82过表达抑制病毒触发的途径活化，而其敲低增强诱导的IFN-β表达。WDR 82位于线粒体上，其第一个N-末端WD 40结构域对于定位至关重要。WDR 82与TNFR相关因子（TRAF）3相互作用，其过表达促进TRAF 3上K48连接而非K63连接的多聚泛素化。此外，WDR 82敲低抑制细胞中的病毒复制，而其过表达具有相反的效果。有趣的是，WDR 82以细胞类型特异性方式调节仙台病毒诱导的IFNB 1表达。综上所述，我们的研究结果表明，WDR 82是通过介导TRAF 3多聚泛素化状态和线粒体稳定性的病毒触发的I型IFN途径的负调节剂。
Upon virus infection, retinoic acid–inducible gene I–like receptors in host cells recognize viral RNA and activate type I IFN expression. Previously, we identified WD repeat domain (WDR) 5 as one positive regulator for pathway activation. In this study, we report that WDR82, a homolog protein of WDR5, acts opposite to WDR5 and inhibits the activation of the retinoic acid–inducible gene I signaling pathway. WDR82 overexpression inhibits virus-triggered pathway activation, whereas its knockdown enhances induced IFN-β expression. WDR82 is localized on the mitochondria, and its first N-terminal WD40 domain is critical for localization. WDR82 interacts with TNFR-associated factor (TRAF) 3, and its overexpression promotes K48-linked, but not K63-linked, polyubiquitination on TRAF3. Furthermore, WDR82 knockdown inhibits viral replication in the cell, whereas its overexpression has the opposite effect. Interestingly, WDR82 regulates Sendai virus–induced IFNB1 expression in a cell type–specific manner. Taken together, our findings demonstrate that WDR82 is a negative regulator of virus-triggered type I IFNs pathway through mediating TRAF3 polyubiquitination status and stability on mitochondria.