Mitofusin 2 inhibits mitochondrial antiviral signaling.
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 kappaB (NF-kappaB). In contrast, loss of endogenous Mfn2 enhanced virus-induced production of IFN-beta 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.
Yasukawa
Kai
K
Department of Biology, Kyushu University, Hakozaki, Higashi-ku, Fukuoka, Japan.
Oshiumi
Hiroyuki
H
Takeda
Makoto
M
Ishihara
Naotada
N
Yanagi
Yusuke
Y
Seya
Tsukasa
T
Kawabata
Shun-ichiro
S
Koshiba
Takumi
T
D048868:Adaptor Proteins, Signal Transducing / Q000235:genetics / Q000378:metabolism*; D000818:Animals; D015153:Blotting, Western; D002460:Cell Line; D002478:Cells, Cultured; D002850:Chromatography, Gel; D005347:Fibroblasts / Q000166:cytology / Q000378:metabolism*; D020558:GTP Phosphohydrolases; D006367:HeLa Cells; D054884:Host-Pathogen Interactions; D006801:Humans; D047468:Immunoprecipitation; D050838:Interferon Regulatory Factor-3 / Q000235:genetics / Q000378:metabolism; D008459:Measles virus / Q000502:physiology; D008565:Membrane Proteins / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D018345:Mice, Knockout; D008928:Mitochondria / Q000378:metabolism* / Q000821:virology; D024101:Mitochondrial Proteins / Q000235:genetics / Q000378:metabolism*; D008954:Models, Biological; D016328:NF-kappa B / Q000235:genetics / Q000378:metabolism; D011485:Protein Binding; D017346:Protein Serine-Threonine Kinases / Q000235:genetics / Q000378:metabolism; D034622:RNA Interference; D048029:TNF Receptor-Associated Factor 6 / Q000235:genetics / Q000378:metabolism; D014162:Transfection
D048868:Adaptor Proteins, Signal Transducing; D050838:Interferon Regulatory Factor-3; C505371:MAVS protein, human; D008565:Membrane Proteins; D024101:Mitochondrial Proteins; D016328:NF-kappa B; D048029:TNF Receptor-Associated Factor 6; D017346:Protein Serine-Threonine Kinases; C403191:TBK1 protein, human; D020558:GTP Phosphohydrolases; C470018:MFN2 protein, human