RLR-mediated antiviral innate immunity requires oxidative phosphorylation activity

Takuma Yoshizumi; Hiromi Imamura; Tomohiro Taku; Takahiro Kuroki; Atsushi Kawaguchi; Kaori Ishikawa; Kazuto Nakada; Takumi Koshiba

doi:10.1038/s41598-017-05808-w

RLR-mediated antiviral innate immunity requires oxidative phosphorylation activity

Sci Rep. 2017 Jul 14;7(1):5379. doi: 10.1038/s41598-017-05808-w.

Authors

Takuma Yoshizumi¹, Hiromi Imamura², Tomohiro Taku³, Takahiro Kuroki³, Atsushi Kawaguchi³, Kaori Ishikawa⁴, Kazuto Nakada⁴, Takumi Koshiba⁵

Affiliations

¹ Department of Biology, Faculty of Science, Kyushu University, 744 Motooka, Nishi-ku, Fukuoka, 819-0395, Japan.
² Graduate School of Biostudies, Kyoto University, Yoshida-konoe-cho, Sakyo-ku, Kyoto, 606-8501, Japan.
³ Department of Infection Biology, Faculty of Medicine and Graduate School of Comprehensive Human Sciences, University of Tsukuba, 1-1-1 Tennodai, Tsukuba, Ibaraki, 305-8575, Japan.
⁴ Faculty of Life and Environmental Sciences, University of Tsukuba, 1-1-1 Tennodai, Tsukuba, Ibaraki, 305-8572, Japan.
⁵ Department of Biology, Faculty of Science, Kyushu University, 744 Motooka, Nishi-ku, Fukuoka, 819-0395, Japan. [email protected].

Abstract

Mitochondria act as a platform for antiviral innate immunity, and the immune system depends on activation of the retinoic acid-inducible gene I (RIG-I)-like receptors (RLR) signaling pathway via an adaptor molecule, mitochondrial antiviral signaling. We report that RLR-mediated antiviral innate immunity requires oxidative phosphorylation (OXPHOS) activity, a prominent physiologic function of mitochondria. Cells lacking mitochondrial DNA or mutant cells with respiratory defects exhibited severely impaired virus-induced induction of interferons and proinflammatory cytokines. Recovery of the OXPHOS activity in these mutants, however, re-established RLR-mediated signal transduction. Using in vivo approaches, we found that mice with OXPHOS defects were highly susceptible to viral infection and exhibited significant lung inflammation. Studies to elucidate the molecular mechanism of OXPHOS-coupled immune activity revealed that optic atrophy 1, a mediator of mitochondrial fusion, contributes to regulate the antiviral immune response. Our findings provide evidence for functional coordination between RLR-mediated antiviral innate immunity and the mitochondrial energy-generating system in mammals.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Animals
Bacterial Proteins / genetics
Bacterial Proteins / metabolism
Cell Line
DEAD Box Protein 58 / genetics
DEAD Box Protein 58 / immunology*
Eye Proteins / genetics
Eye Proteins / immunology
Gene Expression Regulation
Genes, Reporter
Green Fluorescent Proteins / genetics
Green Fluorescent Proteins / metabolism
HEK293 Cells
Host-Pathogen Interactions / immunology*
Humans
Immunity, Innate*
Influenza A virus / growth & development
Influenza A virus / immunology
Interferons / genetics
Interferons / immunology
Luciferases / genetics
Luciferases / metabolism
Luminescent Proteins / genetics
Luminescent Proteins / metabolism
Lung / immunology
Lung / virology
Membrane Glycoproteins / genetics
Membrane Glycoproteins / immunology
Mice
Mice, Inbred C57BL
Mitochondria / immunology*
Mitochondria / metabolism
Mitochondria / virology
Mitochondrial Dynamics / immunology
Oxidative Phosphorylation*
Phagocytes / immunology
Phagocytes / virology
Receptors, G-Protein-Coupled / genetics
Receptors, G-Protein-Coupled / immunology
Receptors, Immunologic
Signal Transduction

Substances

Bacterial Proteins
Cyan Fluorescent Protein
Eye Proteins
Gpr143 protein, mouse
Luminescent Proteins
Membrane Glycoproteins
Receptors, G-Protein-Coupled
Receptors, Immunologic
yellow fluorescent protein, Bacteria
Green Fluorescent Proteins
Interferons
Luciferases
RIGI protein, human
Ddx58 protein, mouse
DEAD Box Protein 58