Blue edges represent novel ppi. MAP1CL3C and SH3GLB1. Strikingly, reduction of IRGM expression using small interfering RNA impairs both Measles computer virus (MeV), Hepatitis C computer virus (HCV) and human immunodeficiency computer 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 proteinsper seis 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. == Author Summary == 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 Laniquidar 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 computer virus (HCV), human immunodeficiency computer virus 1 (HIV-1), Measles computer virus (MeV) and influenza A computer 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. == Introduction == Macroautophagy (thereafter referred to as autophagy) is a highly regulated self-degradative mechanism for Laniquidar intracellular clearance and recycling Rabbit Polyclonal to KAL1 of cytoplasmic Laniquidar contents[1]. During this process large portions of the cytoplasm are engulfed into autophagosomes that subsequently fuse with lysosomes to form acidic autolysosomes where degradation occurs. The autophagy process results from a cascade of reactions orchestrated by autophagy-related genes (atg) encoding ATG proteins mostly defined in yeast and for which numerous mammalian orthologs have been identified[2]. However, the function of most of theseatgremains poorly characterized and several nonatgmammalian genes were also described to regulate autophagy. During autophagy, the formation of an isolation membrane is initiated by class III phophatidylinositol 3-kinase (PIK3C3)/Beclin1 containing complexes[3][5]. The elongation of the isolation membrane involves two ubiquitin-like conjugation systems[6],[7]. In one of them, ATG12 associates with ATG5 for the formation of ATG12-ATG5-ATG16L1 molecular complexes that bind the outer membrane of the isolation membrane. In the second, LC3 is coupled with phosphatidylethanolamine to generate a lipidated LC3-II form that is integrated in both the outer and inner membranes of the autophagosome. Whereas required at a basal level for cellular homeostasis maintenance, autophagy is used as a universal innate cell defense mechanism to fight intracellular pathogens allowing their delivery to degradative lysosomes[8],[9]. Studies involving overexpression or knock-down ofatghave demonstrated an important role for autophagy in both innate antibacterial[10][12]and antiviral defense[13],[14]. Autophagy contributes to immune surveillance via cytoplasmic sampling and delivery of intracellular pathogens or components of these pathogens to endosomes and major histocompatibility complex (MHC)-II molecules rich compartments, thus promoting innate recognition by endosomal Toll-like receptors (TLR)[15]and pathogen-adaptive immune response[16][18], respectively. However, since autophagy is a conserved pathway, intracellular pathogens were submitted to an Laniquidar evolutionary pressure that led to the selection of pathogens with different molecular strategies to avoid or subvert this process to their own benefit[8]. RNA.