TY - JOUR
T1 - Influenza a virus protein PB1-F2 translocates into mitochondria via Tom40 channels and impairs innate immunity
AU - Yoshizumi, Takuma
AU - Ichinohe, Takeshi
AU - Sasaki, Osamu
AU - Otera, Hidenori
AU - Kawabata, Shun Ichiro
AU - Mihara, Katsuyoshi
AU - Koshiba, Takumi
N1 - Funding Information:
We are grateful to Koji Okamoto (the Osaka University, Japan) and Thomas Langer (the University of Cologne) for their valuable comments on the study. We appreciate technical support from the Research Support Centre, the Graduate School of Medical Sciences, the Kyushu University for the fluorescence measurements and Yuko Fuchigami for her technical assistance with DNA cloning and sequencing. The anti-PB1-F2 (A/PR8 strain) monoclonal antibody was a kind gift from Viktor Wixler (the Münster University Hospital Medical School). We are also grateful to Yoshihiro Kawaoka (the University of Tokyo) for kindly providing the pPolI/CA04-PB1-F2-stop88W plasmid and the A/CA/ 04/09 (H1N1) virus, Hideki Hasegawa (the National Institute of Infectious Diseases, Japan) for the A/Beijing/262/95 (H1N1) virus, Michael Whitt (the University of Tennessee) for the recombinant vesicular stomatitis virus and Victoria Allan (the University of Manchester) for the ER-green plasmid. This work was supported by the JSPS KAKENHI Grants (No. 25115515, 26291032, and 26620135 to T.K.), the Kyushu University Interdisciplinary Programs in Education and Projects in Research Development (T.K.), the Uehara Memorial Foundation (T.K.), the Takeda Science Foundation (T.K.), the Kao Foundation for Arts and Sciences (T.K. and T.I.), the Tokyo Biochemical Research Foundation (T.I.), the Mochida Memorial Foundation for Medical and Pharmaceutical Research (T.I.), and the Sasakawa Scientific Research Grant from the Japan Science Society (T.Y.). This study was also partly supported by the Grant for Joint Research Project of the Institute of Medical Science, the University of Tokyo (T.K.) and Research Fellow of the Japan Society for the Promotion of Science (O.S.).
PY - 2014/8/20
Y1 - 2014/8/20
N2 - Mitochondria contribute to cellular innate immunity against RNA viruses. Mitochondrial-mediated innate immunity is regulated by signalling molecules that are recruited to the mitochondrial membrane, and depends on the mitochondrial inner membrane potential (Î "Ï ̂ m). Here we examine the physiological relevance of Î "Ï ̂ m and the mitochondrial-associating influenza A viral protein PB1-F2 in innate immunity. When expressed in host cells, PB1-F2 completely translocates into the mitochondrial inner membrane space via Tom40 channels, and its accumulation accelerates mitochondrial fragmentation due to reduced Î "Ï ̂ m. By contrast, PB1-F2 variants lacking a C-terminal polypeptide, which is frequently found in low pathogenic subtypes, do not affect mitochondrial function. PB1-F2-mediated attenuation of Î "Ï ̂ m suppresses the RIG-I signalling pathway and activation of NLRP3 inflammasomes. PB1-F2 translocation into mitochondria strongly correlates with impaired cellular innate immunity, making this translocation event a potential therapeutic target.
AB - Mitochondria contribute to cellular innate immunity against RNA viruses. Mitochondrial-mediated innate immunity is regulated by signalling molecules that are recruited to the mitochondrial membrane, and depends on the mitochondrial inner membrane potential (Î "Ï ̂ m). Here we examine the physiological relevance of Î "Ï ̂ m and the mitochondrial-associating influenza A viral protein PB1-F2 in innate immunity. When expressed in host cells, PB1-F2 completely translocates into the mitochondrial inner membrane space via Tom40 channels, and its accumulation accelerates mitochondrial fragmentation due to reduced Î "Ï ̂ m. By contrast, PB1-F2 variants lacking a C-terminal polypeptide, which is frequently found in low pathogenic subtypes, do not affect mitochondrial function. PB1-F2-mediated attenuation of Î "Ï ̂ m suppresses the RIG-I signalling pathway and activation of NLRP3 inflammasomes. PB1-F2 translocation into mitochondria strongly correlates with impaired cellular innate immunity, making this translocation event a potential therapeutic target.
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U2 - 10.1038/ncomms5713
DO - 10.1038/ncomms5713
M3 - Article
C2 - 25140902
AN - SCOPUS:84907319179
SN - 2041-1723
VL - 5
JO - Nature communications
JF - Nature communications
M1 - 4713
ER -