title: A structural perspective of the MAVS-regulatory mechanism on the mitochondrial outer membrane using bioluminescence resonance energy transfer.
abstract: In most eukaryotic cells, mitochondria have various essential roles for proper cell function, such as energy production, and in mammals mitochondria also act as a platform for antiviral innate immunity. Mitochondrial-mediated antiviral immunity depends on the activation of the cytoplasmic retinoic acid-inducible gene I (RIG-I)-like receptors (RLRs) signaling pathway, and on the participation of mitochondrial antiviral signaling (MAVS), which is localized on the mitochondrial outer membrane. After RNA virus infection, RLRs translocate to the mitochondrial surface to interact with MAVS, and the adaptor protein undergoes a conformational change that is essential for downstream signaling, although its structural features are poorly understood. Here we examined the MAVS-regulatory mechanism on the mitochondrial outer membrane using bioluminescence resonance energy transfer (BRET) in live cells. Using a combination of BRET and functional analysis, we found that the activated MAVS conformation is a highly ordered oligomer, at least more than three molecules per complex unit on the membrane. Hepatitis C virus NS3/4A protease and mitofusin 2, which are known MAVS inhibitors, interfere with MAVS homotypic oligomerization in a distinct manner, each differentially altering the active conformation of MAVS. Our results reveal structural features underlying the precise regulation of MAVS signaling on the mitochondrial outer membrane, and may provide insight into other signaling systems involving organelles.
authors: Department of Biology, Faculty of Sciences, Kyushu University, Fukuoka, Japan.
authors: Osamu
authors: O
authors: Sasaki
authors: Takuma
authors: T
authors: Yoshizumi
authors: Misa
authors: M
authors: Kuboyama
authors: Takeshi
authors: T
authors: Ishihara
authors: Emiko
authors: E
authors: Suzuki
authors: Shun-ichiro
authors: S
authors: Kawabata
authors: Takumi
authors: T
authors: Koshiba
mesh_terms: D000818:Animals; D060807:Bioluminescence Resonance Energy Transfer Techniques; D000071457:DEAD Box Protein 58; D053487:DEAD-box RNA Helicases / Q000235:genetics / Q000378:metabolism; D004734:Energy Metabolism; D057809:HEK293 Cells; D006801:Humans; D007113:Immunity, Innate / Q000235:genetics; D008928:Mitochondria / Q000235:genetics / Q000378:metabolism; D051336:Mitochondrial Membranes / Q000378:metabolism*; D012327:RNA Virus Infections / Q000235:genetics / Q000378:metabolism; D011971:Receptors, Immunologic; D015398:Signal Transduction; D017361:Viral Nonstructural Proteins / Q000378:metabolism; D012697:Serine Endopeptidases; D043583:Nucleoside-Triphosphatase; D000085242:Viral Proteases
chemical_list: D000071457:DEAD Box Protein 58; D053487:DEAD-box RNA Helicases; D011971:Receptors, Immunologic; D017361:Viral Nonstructural Proteins; C084422:NS3 protein, hepatitis C virus; D012697:Serine Endopeptidases; D043583:Nucleoside-Triphosphatase; D000085242:Viral Proteases; C452820:RIGI protein, human