The mitochondrial ubiquitin ligase MARCH5 resolves MAVS aggregates during antiviral signalling

Young-Suk Yoo, Yong-Yea Park, Jae-Hoon Kim, Hyeseon Cho, Song-Hee Kim, Ho-Soo Lee, Tae-Hwan Kim, You Sun Kim, Youngsoo Lee, Chul-Joong Kim, Jae U Jung, Jong-Soo Lee () and Hyeseong Cho ()
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Young-Suk Yoo: Ajou University School of Medicine, Graduate School of Ajou University
Yong-Yea Park: Ajou University School of Medicine, Graduate School of Ajou University
Jae-Hoon Kim: College of Veterinary Medicine (BK21 Plus Program), Chungnam National University
Hyeseon Cho: Mucosal Immunobiology Section, Laboratory of Molecular Immunology, NIAID, NIH
Song-Hee Kim: Ajou University School of Medicine, Graduate School of Ajou University
Ho-Soo Lee: Ajou University School of Medicine, Graduate School of Ajou University
Tae-Hwan Kim: College of Veterinary Medicine (BK21 Plus Program), Chungnam National University
You Sun Kim: Ajou University School of Medicine, Graduate School of Ajou University
Youngsoo Lee: Graduate School of Ajou University
Chul-Joong Kim: College of Veterinary Medicine (BK21 Plus Program), Chungnam National University
Jae U Jung: Keck School of Medicine, University of Southern California
Jong-Soo Lee: College of Veterinary Medicine (BK21 Plus Program), Chungnam National University
Hyeseong Cho: Ajou University School of Medicine, Graduate School of Ajou University

Nature Communications, 2015, vol. 6, issue 1, 1-14

Abstract: 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 (MARCH5H43W), 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.

Date: 2015
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DOI: 10.1038/ncomms8910

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