IRGM is a common target of RNA viruses that subvert the autophagy network.
IRGM is a common target of RNA viruses that subvert the autophagy network.
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DOI：
10.1371/journal.ppat.1002422
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发表时间：
2011-12
期刊：
影响因子：
6.7
通讯作者：
Faure M
中科院分区：
文献类型：
--
作者：
Grégoire IP;Richetta C;Meyniel-Schicklin L;Borel S;Pradezynski F;Diaz O;Deloire A;Azocar O;Baguet J;Le Breton M;Mangeot PE;Navratil V;Joubert PE;Flacher M;Vidalain PO;André P;Lotteau V;Biard-Piechaczyk M;Rabourdin-Combe C;Faure M
自噬是一种保守的降解途径，是宿主抵抗细胞内病原体的一种防御机制。然而，一些病毒可以逃避或破坏自噬，以确保自己的复制。尽管如此，病毒与自噬相互作用的分子细节在很大程度上仍然未知。我们已经确定了83个蛋白质的几个家庭的RNA病毒（副粘病毒科，黄病毒科，正粘病毒科，逆转录病毒科和披膜病毒科），相互作用的能力与44人类自噬相关蛋白，使用酵母双杂交和生物信息学分析。我们发现自噬网络是RNA病毒高度靶向的。虽然是自噬的核心，但靶向蛋白质也与其他细胞功能的蛋白质有大量的连接。有趣的是，免疫相关的GT3家族M（IRGM），最靶向的蛋白，被发现与自噬相关蛋白ATG 5，ATG 10，MAP 1CL 3C和SH 3GLB 1相互作用。引人注目的是，使用小干扰RNA减少IRGM表达会损害麻疹病毒（MeV）、丙型肝炎病毒（HCV）和人类免疫缺陷病毒-1（HIV-1）诱导的自噬和病毒颗粒产生。此外，我们发现，IRGM相互作用MeV-C，HCV-NS 3或HIV-NEF蛋白本身的表达足以通过IRGM依赖性途径诱导自噬。我们的工作揭示了IRGM在病毒诱导的自噬中的意想不到的作用，并表明几种不同的RNA病毒家族可能使用共同的策略来操纵自噬以提高病毒感染性。自噬是一种高度调节的细胞降解途径，用于回收长寿命蛋白质和受损细胞器。自噬也被宿主细胞用作对抗细胞内病原体的防御机制。自噬可以降解病原体或病原体衍生的分子，这些分子被困在称为自噬体的专门囊泡中。病毒和病毒蛋白也不例外。然而，由于自噬是一个保守的途径，病毒受到进化的压力，导致选择避免或破坏这一过程的分子策略，以促进病毒复制。然而，病毒与自噬相互作用的分子细节仍然是未知的。我们确定了几个RNA病毒家族（包括丙型肝炎病毒（HCV），人类免疫缺陷病毒1（HIV-1），麻疹病毒（MeV）和甲型流感病毒）的83种蛋白质与已知调节自噬的44种人类蛋白质相互作用的能力，并发现自噬是RNA病毒的高度靶向。引人注目的是，免疫相关的GT3家族M（IRGM），以其在抗细菌自噬中的作用而闻名，是最具靶向的自噬蛋白。它的缺乏对HCV、HIV-1和MeV的产生是有害的。因此，我们的数据表明，不同的RNA病毒家族使用类似的策略来微调自噬以使其自身受益。
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. Autophagy is a highly regulated cellular degradative pathway for recycling of long-lived proteins and damaged organelles. Autophagy is also used by host cells as a defense mechanism against intracellular pathogens. Autophagy can degrade pathogens or pathogen-derived molecules trapped within specialized vesicles named autophagosomes. Viruses and viral proteins are not an exception. However, since autophagy is a conserved pathway, viruses were submitted to an evolutionary pressure that led to the selection of molecular strategies which avoid or subvert this process to promote viral replication. Nevertheless the molecular details of viral interaction with autophagy remain largely unknown. We determined the ability of 83 proteins of several families of RNA viruses (including Hepatitis C virus (HCV), human immunodeficiency virus 1 (HIV-1), Measles virus (MeV) and influenza A virus) to interact with 44 human proteins known to regulate autophagy and found that autophagy is highly targeted by RNA viruses. Strikingly, immunity-associated GTPase family M (IRGM), known for its role in autophagy against bacteria, is the most targeted autophagy protein. Its absence is detrimental for HCV, HIV-1 and MeV production. Therefore, our data show that different RNA viruses families use similar strategies to fine tune autophagy to their own benefit.
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