A structural perspective of the MAVS-regulatory mechanism on the mitochondrial outer membrane using bioluminescence resonance energy transfer

Osamu Sasaki, Takuma Yoshizumi, Misa Kuboyama, Takeshi Ishihara, Emiko Suzuki, Shun-Ichiro Kawabata, Takumi Koshiba

Research output: Contribution to journalArticle

17 Citations (Scopus)

Abstract

In most eukaryotic cells, mitochondria have various essential roles for proper cell function, such as energy production, and in mammals mitochondria also act as a platform for antiviral innate immunity. Mitochondrial-mediated antiviral immunity depends on the activation of the cytoplasmic retinoic acid-inducible gene I (RIG-I)-like receptors (RLRs) signaling pathway, and on the participation of mitochondrial antiviral signaling (MAVS), which is localized on the mitochondrial outer membrane. After RNA virus infection, RLRs translocate to the mitochondrial surface to interact with MAVS, and the adaptor protein undergoes a conformational change that is essential for downstream signaling, although its structural features are poorly understood. Here we examined the MAVS-regulatory mechanism on the mitochondrial outer membrane using bioluminescence resonance energy transfer (BRET) in live cells. Using a combination of BRET and functional analysis, we found that the activated MAVS conformation is a highly ordered oligomer, at least more than three molecules per complex unit on the membrane. Hepatitis C virus NS3/4A protease and mitofusin 2, which are known MAVS inhibitors, interfere with MAVS homotypic oligomerization in a distinct manner, each differentially altering the active conformation of MAVS. Our results reveal structural features underlying the precise regulation of MAVS signaling on the mitochondrial outer membrane, and may provide insight into other signaling systems involving organelles.

Original languageEnglish
Pages (from-to)1017-1027
Number of pages11
JournalBiochimica et Biophysica Acta - Molecular Cell Research
Volume1833
Issue number5
DOIs
Publication statusPublished - May 1 2013

All Science Journal Classification (ASJC) codes

  • Cell Biology
  • Molecular Biology

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