title: Mitochondrial-associated endoplasmic reticulum membranes (MAM) form innate immune synapses and are targeted by hepatitis C virus.
abstract: RIG-I is a cytosolic pathogen recognition receptor that engages viral RNA in infected cells to trigger innate immune defenses through its adaptor protein MAVS. MAVS resides on mitochondria and peroxisomes, but how its signaling is coordinated among these organelles has not been defined. Here we show that a major site of MAVS signaling is the mitochondrial-associated membrane (MAM), a distinct membrane compartment that links the endoplasmic reticulum to mitochondria. During RNA virus infection, RIG-I is recruited to the MAM to bind MAVS. Dynamic MAM tethering to mitochondria and peroxisomes then coordinates MAVS localization to form a signaling synapse between membranes. Importantly, the hepatitis C virus NS3/4A protease, which cleaves MAVS to support persistent infection, targets this synapse for MAVS proteolysis from the MAM, but not from mitochondria, to ablate RIG-I signaling of immune defenses. Thus, the MAM mediates an intracellular immune synapse that directs antiviral innate immunity.
authors.affiliation: Department of Immunology, University of Washington School of Medicine, Seattle, WA 98195, USA.
authors.forename: Stacy M
authors.initials: SM
authors.lastname: Horner
authors.forename: Helene Minyi
authors.initials: HM
authors.lastname: Liu
authors.forename: Hae Soo
authors.initials: HS
authors.lastname: Park
authors.forename: Jessica
authors.initials: J
authors.lastname: Briley
authors.forename: Michael
authors.initials: M
authors.lastname: Gale
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000502:physiology; D000071457:DEAD Box Protein 58; D053487:DEAD-box RNA Helicases / Q000502:physiology; D004721:Endoplasmic Reticulum / Q000502:physiology*; D016174:Hepacivirus / Q000276:immunology*; D006801:Humans; D007113:Immunity, Innate; D054992:Immunological Synapses / Q000502:physiology*; D007425:Intracellular Membranes / Q000502:physiology*; D008928:Mitochondria / Q000502:physiology*; D011971:Receptors, Immunologic; D017361:Viral Nonstructural Proteins / Q000032:analysis / Q000502:physiology; D012697:Serine Endopeptidases; D043583:Nucleoside-Triphosphatase; D000085242:Viral Proteases
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D000071457:DEAD Box Protein 58; D053487:DEAD-box RNA Helicases; D011971:Receptors, Immunologic; D017361:Viral Nonstructural Proteins; C505371:MAVS protein, human; C084422:NS3 protein, hepatitis C virus; D012697:Serine Endopeptidases; D043583:Nucleoside-Triphosphatase; D000085242:Viral Proteases; C080107:NS4B protein, flavivirus; C452820:RIGI protein, human