A novel selective autophagy receptor, CCDC50, delivers K63 polyubiquitination-activated RIG-I/MDA5 for degradation during viral infection
A novel selective autophagy receptor, CCDC50, delivers K63 polyubiquitination-activated RIG-I/MDA5 for degradation during viral infection
复制标题
一种新型选择性自噬受体 CCDC50，可传递 K63 多聚泛素化激活的 RIG-I/MDA5，以便在病毒感染期间降解
DOI：
10.1038/s41422-020-0362-1
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发表时间：
2020-07-01
期刊：
影响因子：
44.1
通讯作者：
Guo, Deyin
中科院分区：
文献类型：
--
作者：
Hou, Panpan;Yang, Kongxiang;Guo, Deyin
自噬是一个保守的过程，它将胞液物质运送到溶酶体进行降解，但它在抗病毒天然免疫调节中的直接作用仍然知之甚少。在这里，通过高通量筛选，我们发现CCDC50是一种以前未知的自噬受体，它负向调节由RIG-I样受体(RIG-I-like Receptor，RLR)启动的I型干扰素(IFN)信号通路，RIG-I样受体是RNA病毒的传感器。CCDC50的表达被病毒感染增强，CCDC50特异性识别K63-多泛素化的RLR，从而传递激活的RIG-I/MDA5进行自噬降解。晶体结构分析证实了CCDC50与吞噬体膜蛋白Lc3的结合。与其他已知的与LIR对接位点(LDS)或Lc3的UIM对接位点(UDS)相关的自噬货物受体不同，CCDC50可以与LDS和UDS结合，代表了一种新型的货物受体。在RNA病毒感染的小鼠模型中，CCDC50缺乏降低了RIG-I/MDA5的自噬降解，并促进了I型干扰素反应，从而增强了病毒抵抗力，提高了存活率。这些结果揭示了自噬和抗病毒先天免疫反应之间的新联系，并为RLR介导的抗病毒信号的调控机制提供了更多的见解。
Autophagy is a conserved process that delivers cytosolic substances to the lysosome for degradation, but its direct role in the regulation of antiviral innate immunity remains poorly understood. Here, through high-throughput screening, we discovered that CCDC50 functions as a previously unknown autophagy receptor that negatively regulates the type I interferon (IFN) signaling pathway initiated by RIG-I-like receptors (RLRs), the sensors for RNA viruses. The expression of CCDC50 is enhanced by viral infection, and CCDC50 specifically recognizes K63-polyubiquitinated RLRs, thus delivering the activated RIG-I/MDA5 for autophagic degradation. The association of CCDC50 with phagophore membrane protein LC3 is confirmed by crystal structure analysis. In contrast to other known autophagic cargo receptors that associate with either the LIR-docking site (LDS) or the UIM-docking site (UDS) of LC3, CCDC50 can bind to both LDS and UDS, representing a new type of cargo receptor. In mouse models with RNA virus infection, CCDC50 deficiency reduces the autophagic degradation of RIG-I/MDA5 and promotes type I IFN responses, resulting in enhanced viral resistance and improved survival rates. These results reveal a new link between autophagy and antiviral innate immune responses and provide additional insights into the regulatory mechanisms of RLR-mediated antiviral signaling.