title: Regulation of mitochondrial antiviral signaling (MAVS) expression and signaling by the mitochondria-associated endoplasmic reticulum membrane (MAM) protein Gp78.
abstract: In a previous study, we identified the E3 ubiquitin ligase Gp78 by RNAi high-throughput screening as a gene whose depletion restricted enterovirus infection. In the current study, we show that Gp78, which localizes to the ER-mitochondria interface, is a regulator of RIG-I-like receptor (RLR) antiviral signaling. We show that depletion of Gp78 results in a robust decrease of vesicular stomatitis virus (VSV) infection and a corresponding enhancement of type I interferon (IFN) signaling. Mechanistically, we show that Gp78 modulates type I IFN induction by altering both the expression and signaling of the mitochondria-localized RLR adaptor mitochondrial antiviral signaling (MAVS). Expression of mutants of Gp78 that abolish its E3 ubiquitin ligase and its participation in ER-associated degradation (ERAD) lost their ability to degrade MAVS, but surprisingly maintained their ability to repress RLR signaling. In contrast, Gp78 lacking its entire C terminus lost both its ability to degrade MAVS and repress RLR signaling. We show that Gp78 interacts with both the N- and C-terminal domains of MAVS via its C-terminal RING domain, and that this interaction is required to abrogate Gp78-mediated attenuation of MAVS signaling. Our data thus implicate two parallel pathways by which Gp78 regulates MAVS signaling; one pathway requires its E3 ubiquitin ligase and ERAD activity to directly degrade MAVS, whereas the other pathway occurs independently of these activities, but requires the Gp78 RING domain and occurs via a direct association between this region and MAVS.
authors.affiliation: From the Department of Infectious Diseases and Microbiology, Graduate School of Public Health.
authors.forename: Jana L
authors.initials: JL
authors.lastname: Jacobs
authors.forename: Jianzhong
authors.initials: J
authors.lastname: Zhu
authors.forename: Saumendra N
authors.initials: SN
authors.lastname: Sarkar
authors.forename: Carolyn B
authors.initials: CB
authors.lastname: Coyne
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000235:genetics / Q000378:metabolism*; D045744:Cell Line, Tumor; D060746:Endoplasmic Reticulum-Associated Degradation / Q000502:physiology*; D005786:Gene Expression Regulation / Q000502:physiology; D006801:Humans; D007370:Interferon Type I / Q000096:biosynthesis / Q000235:genetics; D017434:Protein Structure, Tertiary; D060285:Receptors, Autocrine Motility Factor / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction / Q000502:physiology*
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D007370:Interferon Type I; C505371:MAVS protein, human; C555000:AMFR protein, human; D060285:Receptors, Autocrine Motility Factor
keywords: Antiviral Signaling; ERad; Gp78; Interferon; MAM; MAVS; Mitochondria; RNA Viruses; Rig-like receptors (RLR)