Mitochondrial protein mitofusin 2 is required for NLRP3 inflammasome activation after RNA virus infection

Takeshi Ichinohe, Tatsuya Yamazaki, Takumi Koshiba, Yusuke Yanagi

Research output: Contribution to journalArticle

102 Citations (Scopus)

Abstract

Nod-like receptor family, pyrin domain-containing 3 (NLRP3), is involved in the early stages of the inflammatory response by sensing cellular damage or distress due to viral or bacterial infection. Activation of NLRP3 triggers its assembly into a multimolecular protein complex, termed "NLRP3 inflammasome." This event leads to the activation of the downstream molecule caspase- 1 that cleaves the precursor forms of proinflammatory cytokines, such as interleukin 1 beta (IL-1β) and IL-18, and initiates the immune response. Recent studies indicate that the reactive oxygen species produced by mitochondrial respiration is critical for the activation of the NLRP3 inflammasome by monosodium urate, alum, and ATP. However, the precise mechanism by which RNA viruses activate the NLRP3 inflammasome is not well understood. Here, we show that loss of mitochondrial membrane potential [δ(m)] dramatically reduced IL-1β secretion after infection with influenza, measles, or encephalomyocarditis virus (EMCV). Reduced IL-1β secretion was also observed following overexpression of the mitochondrial inner membrane protein, uncoupling protein- 2, which induces mitochondrial proton leakage and dissipates δ(m). δ(m) was required for association between the NLRP3 and mitofusin 2, a mediator of mitochondrial fusion, after infection with influenza virus or EMCV. Importantly, the knockdown of mitofusin 2 significantly reduced the secretion of IL-1β after infection with influenza virus or EMCV. Our results provide insight into the roles of mitochondria in NLRP3 inflammasome activation.

Original languageEnglish
Pages (from-to)17963-17968
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Volume110
Issue number44
DOIs
Publication statusPublished - Oct 29 2013

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