Format

Send to

Choose Destination
Nat Commun. 2015 Aug 6;6:7910. doi: 10.1038/ncomms8910.

The mitochondrial ubiquitin ligase MARCH5 resolves MAVS aggregates during antiviral signalling.

Author information

1
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.
2
Department of Biochemistry, Ajou University School of Medicine, 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
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.
6
Department of Molecular Microbiology and Immunology, Keck School of Medicine, University of Southern California, Los Angeles, California 90089, USA.
7
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.

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.

PMID:
26246171
PMCID:
PMC4918326
DOI:
10.1038/ncomms8910
[Indexed for MEDLINE]
Free PMC Article

Supplemental Content

Full text links

Icon for Nature Publishing Group Icon for PubMed Central
Loading ...
Support Center