title: The mitochondrial ubiquitin ligase MARCH5 resolves MAVS aggregates during antiviral signalling.
abstract: Mitochondria serve as platforms for innate immunity. The mitochondrial antiviral signalling (MAVS) protein forms aggregates that elicit robust type-I interferon induction on viral infection, but persistent MAVS signalling leads to host immunopathology; it remains unknown how these signalling aggregates are resolved. Here we identify the mitochondria-resident E3 ligase, MARCH5, as a negative regulator of MAVS aggregates. March5(+/-) mice and MARCH5-deficient immune cells exhibit low viral replication and elevated type-I interferon responses to RNA viruses. MARCH5 binds MAVS only during viral stimulation when MAVS forms aggregates, and these interactions require the RING domain of MARCH5 and the CARD domain of MAVS. MARCH5, but not its RING mutant (MARCH5(H43W)), reduces the level of MAVS aggregates. MARCH5 transfers ubiquitin to Lys7 and Lys500 of MAVS and promotes its proteasome-mediated degradation. Our results indicate that MARCH5 modulates MAVS-mediated antiviral signalling, preventing excessive immune reactions.
authors.affiliation: 1] Department of Biochemistry, Ajou University School of Medicine, Graduate School of Ajou University, Suwon 443-380, Korea [2] Department of Biological Sciences, Graduate School of Ajou University, Suwon 443-380, Korea.
authors.forename: Young-Suk
authors.initials: YS
authors.lastname: Yoo
authors.affiliation: Department of Biochemistry, Ajou University School of Medicine, Graduate School of Ajou University, Suwon 443-380, Korea.
authors.forename: Yong-Yea
authors.initials: YY
authors.lastname: Park
authors.affiliation: College of Veterinary Medicine (BK21 Plus Program), Chungnam National University, Daejeon 305-764, Korea.
authors.forename: Jae-Hoon
authors.initials: JH
authors.lastname: Kim
authors.affiliation: Mucosal Immunobiology Section, Laboratory of Molecular Immunology, NIAID, NIH, Bethesda, Maryland 20852, USA.
authors.forename: Hyeseon
authors.initials: H
authors.lastname: Cho
authors.affiliation: Department of Biochemistry, Ajou University School of Medicine, Graduate School of Ajou University, Suwon 443-380, Korea.
authors.forename: Song-Hee
authors.initials: SH
authors.lastname: Kim
authors.affiliation: 1] Department of Biochemistry, Ajou University School of Medicine, Graduate School of Ajou University, Suwon 443-380, Korea [2] Department of Biological Sciences, Graduate School of Ajou University, Suwon 443-380, Korea.
authors.forename: Ho-Soo
authors.initials: HS
authors.lastname: Lee
authors.affiliation: College of Veterinary Medicine (BK21 Plus Program), Chungnam National University, Daejeon 305-764, Korea.
authors.forename: Tae-Hwan
authors.initials: TH
authors.lastname: Kim
authors.affiliation: 1] Department of Biochemistry, Ajou University School of Medicine, Graduate School of Ajou University, Suwon 443-380, Korea [2] Department of Biological Sciences, Graduate School of Ajou University, Suwon 443-380, Korea.
authors.forename: You
authors.initials: Y
authors.lastname: Sun Kim
authors.affiliation: 1] Department of Biological Sciences, Graduate School of Ajou University, Suwon 443-380, Korea [2] Genomic Instability Research Center, Ajou University School of Medicine, Suwon 443-380, Korea.
authors.forename: Youngsoo
authors.initials: Y
authors.lastname: Lee
authors.affiliation: College of Veterinary Medicine (BK21 Plus Program), Chungnam National University, Daejeon 305-764, Korea.
authors.forename: Chul-Joong
authors.initials: CJ
authors.lastname: Kim
authors.affiliation: Department of Molecular Microbiology and Immunology, Keck School of Medicine, University of Southern California, Los Angeles, California 90089, USA.
authors.forename: Jae U
authors.initials: JU
authors.lastname: Jung
authors.affiliation: College of Veterinary Medicine (BK21 Plus Program), Chungnam National University, Daejeon 305-764, Korea.
authors.forename: Jong-Soo
authors.initials: JS
authors.lastname: Lee
authors.affiliation: 1] Department of Biochemistry, Ajou University School of Medicine, Graduate School of Ajou University, Suwon 443-380, Korea [2] Department of Biological Sciences, Graduate School of Ajou University, Suwon 443-380, Korea [3] Genomic Instability Research Center, Ajou University School of Medicine, Suwon 443-380, Korea.
authors.forename: Hyeseong
authors.initials: H
authors.lastname: Cho
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000378:metabolism*; D000818:Animals; D057809:HEK293 Cells; D006801:Humans; D007113:Immunity, Innate; D007370:Interferon Type I / Q000378:metabolism; D008565:Membrane Proteins / Q000378:metabolism*; D008810:Mice, Inbred C57BL; D008928:Mitochondria / Q000201:enzymology; D024101:Mitochondrial Proteins / Q000378:metabolism*; D012327:RNA Virus Infections / Q000276:immunology*; D025801:Ubiquitin / Q000378:metabolism; D044767:Ubiquitin-Protein Ligases / Q000378:metabolism*
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D007370:Interferon Type I; D008565:Membrane Proteins; D024101:Mitochondrial Proteins; D025801:Ubiquitin; D044767:Ubiquitin-Protein Ligases; C512612:MAVS protein, mouse; C505371:MAVS protein, human; C515578:MARCHF5 protein, human; C581898:Marchf5 protein, mouse