IRGM Is a Common Target of RNA Viruses that Subvert the Autophagy Network

Autophagy is a conserved degradative pathway used as a host defense mechanism against intracellular pathogens. However, several viruses can evade or subvert autophagy to insure their own replication. Nevertheless, the molecular details of viral interaction with autophagy remain largely unknown. We have determined the ability of 83 proteins of several families of RNA viruses (Paramyxoviridae, Flaviviridae, Orthomyxoviridae, Retroviridae and Togaviridae), to interact with 44 human autophagy-associated proteins using yeast two-hybrid and bioinformatic analysis. We found that the autophagy network is highly targeted by RNA viruses. Although central to autophagy, targeted proteins have also a high number of connections with proteins of other cellular functions. Interestingly, immunity-associated GTPase family M (IRGM), the most targeted protein, was found to interact with the autophagy-associated proteins ATG5, ATG10, MAP1CL3C and SH3GLB1. Strikingly, reduction of IRGM expression using small interfering RNA impairs both Measles virus (MeV), Hepatitis C virus (HCV) and human immunodeficiency virus-1 (HIV-1)-induced autophagy and viral particle production. Moreover we found that the expression of IRGM-interacting MeV-C, HCV-NS3 or HIV-NEF proteins per se is sufficient to induce autophagy, through an IRGM dependent pathway. Our work reveals an unexpected role of IRGM in virus-induced autophagy and suggests that several different families of RNA viruses may use common strategies to manipulate autophagy to improve viral infectivity.

细胞自噬（Autophagy）是一类保守的降解通路，可作为对抗胞内病原体的宿主防御机制。不过，多种病毒可逃逸或劫持细胞自噬以保障自身复制，但目前病毒与细胞自噬互作的分子细节仍鲜为人知。
本研究通过酵母双杂交（yeast two-hybrid）与生物信息学分析（bioinformatic analysis），检测了副黏病毒科（Paramyxoviridae）、黄病毒科（Flaviviridae）、正黏病毒科（Orthomyxoviridae）、逆转录病毒科（Retroviridae）以及披膜病毒科（Togaviridae）等多个RNA病毒科共83种蛋白与44种人源细胞自噬相关蛋白的互作能力。研究发现，RNA病毒可高度靶向细胞自噬调控网络。尽管这些靶向蛋白是细胞自噬的核心组分，它们同时也与其他细胞功能相关蛋白存在大量互作关联。
有趣的是，免疫相关GTP酶家族M（Immunity-associated GTPase family M, IRGM）是被靶向程度最高的宿主蛋白，可与细胞自噬相关蛋白ATG5、ATG10、MAP1CL3C及SH3GLB1发生互作。值得注意的是，通过小干扰RNA（small interfering RNA, siRNA）降低IRGM的表达，可同时削弱麻疹病毒（Measles virus, MeV）、丙型肝炎病毒（Hepatitis C virus, HCV）及人类免疫缺陷病毒1型（human immunodeficiency virus-1, HIV-1）诱导的细胞自噬过程与病毒粒子的产生。此外，本研究发现，仅表达与IRGM互作的MeV-C、HCV-NS3或HIV-NEF蛋白，即可通过IRGM依赖通路诱导细胞自噬。
本研究揭示了IRGM在病毒诱导细胞自噬过程中此前未被认知的作用，并提示多个不同科的RNA病毒可能通过共用一套调控策略操纵细胞自噬，以提升病毒感染能力。