Virus-infection or 5'ppp-RNA activates antiviral signal through redistribution of IPS-1 mediated by MFN1.
In virus-infected cells, RIG-I-like receptor (RLR) recognizes cytoplasmic viral RNA and triggers innate immune responses including production of type I and III interferon (IFN) and the subsequent expression of IFN-inducible genes. Interferon-beta promoter stimulator 1 (IPS-1, also known as MAVS, VISA and Cardif) is a downstream molecule of RLR and is expressed on the outer membrane of mitochondria. While it is known that the location of IPS-1 is essential to its function, its underlying mechanism is unknown. Our aim in this study was to delineate the function of mitochondria so as to identify more precisely its role in innate immunity. In doing so we discovered that viral infection as well as transfection with 5'ppp-RNA resulted in the redistribution of IPS-1 to form speckle-like aggregates in cells. We further found that Mitofusin 1 (MFN1), a key regulator of mitochondrial fusion and a protein associated with IPS-1 on the outer membrane of mitochondria, positively regulates RLR-mediated innate antiviral responses. Conversely, specific knockdown of MFN1 abrogates both the virus-induced redistribution of IPS-1 and IFN production. Our study suggests that mitochondria participate in the segregation of IPS-1 through their fusion processes.
Onoguchi
Kazuhide
K
Department of Molecular Genetics, Institute for Virus Research, Kyoto University, Kyoto, Japan.
Onomoto
Koji
K
Takamatsu
Shiori
S
Jogi
Michihiko
M
Takemura
Azumi
A
Morimoto
Shiho
S
Julkunen
Ilkka
I
Namiki
Hideo
H
Yoneyama
Mitsutoshi
M
Fujita
Takashi
T
D048868:Adaptor Proteins, Signal Transducing / Q000276:immunology* / Q000378:metabolism; D000818:Animals; D002460:Cell Line; D020558:GTP Phosphohydrolases / Q000276:immunology*; D006801:Humans; D007113:Immunity, Innate; D026901:Membrane Transport Proteins / Q000276:immunology*; D051379:Mice; D008928:Mitochondria / Q000276:immunology / Q000473:pathology; D033681:Mitochondrial Membrane Transport Proteins; D024101:Mitochondrial Proteins / Q000276:immunology*; D012367:RNA, Viral
D048868:Adaptor Proteins, Signal Transducing; C505371:MAVS protein, human; D026901:Membrane Transport Proteins; D033681:Mitochondrial Membrane Transport Proteins; D024101:Mitochondrial Proteins; D012367:RNA, Viral; D020558:GTP Phosphohydrolases; C470017:Mfn1 protein, human