Young-Suk Yoo1,2,*, Yong-Yea Park1,*, Jae-Hoon Kim3, Hyeseon Cho4, Song-Hee Kim1, Ho-Soo Lee1,2, Tae-Hwan Kim3, You Sun Kim1,2, Youngsoo Lee2,5, Chul-Joong Kim3, Jae U. Jung6, Jong-Soo Lee3 & Hyeseong Cho1,2,5
12 Department of Biological Sciences, Graduate School of Ajou University, Suwon 443-380, Korea. 3 College of Veterinary Medicine (BK21 Plus Program), Chungnam National University, Daejeon 305-764, Korea. 4 Mucosal Immunobiology Section, Laboratory of Molecular Immunology, NIAID, NIH, Bethesda, Maryland 20852, USA. 5 Genomic Instability Research Center, Ajou University School of Medicine, Suwon 443-380, Korea. 6 Department of Molecular Microbiology and Immunology, Keck School of Medicine, University of Southern California, Los Angeles, California 90089, USA.
* These authors contributed equally to this work.
Correspondence to : Jong-Soo Lee or Hyeseong Cho
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.