The mitochondrial ubiquitin ligase MARCH5 resolves MAVS aggregates during antiviral signalling

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. RNA viral infections trigger an immune response mediated by the formation of aggregates of the MAVS protein. Here the authors show that the mitochondrial protein MARCH5 modulates this response by transferring ubiquitin to MAVS aggregates, thus promoting their proteasomal degradation.

• Publication year

  2015

• Venue

  Nature Communications

• Publication date

  2015-08-06

• Fields of study

  Biology, Medicine

• Identifiers
  DOI 10.1038/ncomms8910PMID 26246171PMCID 4918326
• External record

  Open on Semantic Scholar

• Source metadata

  Semantic Scholar, PubMed

• No claims are published for this paper.

• No concepts are published for this paper.

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