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Sci. Signal., 18 August 2009
Vol. 2, Issue 84, p. ra47
[DOI: 10.1126/scisignal.2000287]

RESEARCH

Mitofusin 2 Inhibits Mitochondrial Antiviral Signaling

Kai Yasukawa1, Hiroyuki Oshiumi2, Makoto Takeda3, Naotada Ishihara4, Yusuke Yanagi3, Tsukasa Seya2, Shun-ichiro Kawabata1, and Takumi Koshiba1*

1 Department of Biology, Faculty of Sciences, Kyushu University, 6-10-1 Hakozaki, Higashi-ku, Fukuoka 812-8581, Japan.
2 Department of Microbiology and Immunology, Graduate School of Medicine, Hokkaido University, Kita-ku, Sapporo 060-8638, Japan.
3 Department of Virology, Faculty of Medicine, Kyushu University, Higashi-ku, Fukuoka 812-8582, Japan.
4 Department of Physiology and Cell Biology, Tokyo Medical and Dental University, Tokyo 113-8519, Japan.

Abstract: The innate immune response to viral infection involves the activation of multiple signaling steps that culminate in the production of type I interferons (IFNs). Mitochondrial antiviral signaling (MAVS), a mitochondrial outer membrane adaptor protein, plays an important role in this process. Here, we report that mitofusin 2 (Mfn2), a mediator of mitochondrial fusion, interacts with MAVS to modulate antiviral immunity. Overexpression of Mfn2 resulted in the inhibition of retinoic acid–inducible gene I (RIG-I) and melanoma differentiation–associated gene 5 (MDA-5), two cytosolic sensors of viral RNA, as well as of MAVS-mediated activation of the transcription factors interferon regulatory factor 3 (IRF-3) and nuclear factor {kappa}B (NF-{kappa}B). In contrast, loss of endogenous Mfn2 enhanced virus-induced production of IFN-β and thereby decreased viral replication. Structure-function analysis revealed that Mfn2 interacted with the carboxyl-terminal region of MAVS through a heptad repeat region, providing a structural perspective on the regulation of the mitochondrial antiviral response. Our results suggest that Mfn2 acts as an inhibitor of antiviral signaling, a function that may be distinct from its role in mitochondrial dynamics.

* To whom correspondence should be addressed. E-mail: koshiba{at}kyudai.jp

Citation: K. Yasukawa, H. Oshiumi, M. Takeda, N. Ishihara, Y. Yanagi, T. Seya, S.-i. Kawabata, T. Koshiba, Mitofusin 2 Inhibits Mitochondrial Antiviral Signaling. Sci. Signal. 2, ra47 (2009).

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