title: Influenza A virus protein PB1-F2 translocates into mitochondria via Tom40 channels and impairs innate immunity.
abstract: 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 (Δψm). Here we examine the physiological relevance of Δψm 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 Δψm. 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 Δψm 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.
authors.affiliation: Department of Biology, Faculty of Sciences, Kyushu University, 6-10-1 Hakozaki, Fukuoka 812-8581, Japan.
authors.forename: Takuma
authors.initials: T
authors.lastname: Yoshizumi
authors.affiliation: Division of Viral Infection, Department of Infectious Disease Control, International Research Center for Infectious Diseases, Institute of Medical Science, The University of Tokyo, Tokyo 108-8639, Japan.
authors.forename: Takeshi
authors.initials: T
authors.lastname: Ichinohe
authors.affiliation: Department of Biology, Faculty of Sciences, Kyushu University, 6-10-1 Hakozaki, Fukuoka 812-8581, Japan.
authors.forename: Osamu
authors.initials: O
authors.lastname: Sasaki
authors.affiliation: Department of Molecular Biology, Graduate School of Medical Science, Kyushu University, Fukuoka 812-8582, Japan.
authors.forename: Hidenori
authors.initials: H
authors.lastname: Otera
authors.affiliation: Department of Biology, Faculty of Sciences, Kyushu University, 6-10-1 Hakozaki, Fukuoka 812-8581, Japan.
authors.forename: Shun-ichiro
authors.initials: S
authors.lastname: Kawabata
authors.affiliation: Department of Molecular Biology, Graduate School of Medical Science, Kyushu University, Fukuoka 812-8582, Japan.
authors.forename: Katsuyoshi
authors.initials: K
authors.lastname: Mihara
authors.affiliation: Department of Biology, Faculty of Sciences, Kyushu University, 6-10-1 Hakozaki, Fukuoka 812-8581, Japan.
authors.forename: Takumi
authors.initials: T
authors.lastname: Koshiba
mesh_terms: D002352:Carrier Proteins / Q000235:genetics / Q000276:immunology; D045744:Cell Line, Tumor; D000071457:DEAD Box Protein 58; D053487:DEAD-box RNA Helicases / Q000235:genetics / Q000276:immunology; D005786:Gene Expression Regulation; D057809:HEK293 Cells; D006367:HeLa Cells; D054884:Host-Pathogen Interactions / Q000276:immunology; D006801:Humans; D007113:Immunity, Innate; D058847:Inflammasomes / Q000235:genetics / Q000276:immunology; D053118:Influenza A Virus, H1N1 Subtype / Q000737:chemistry / Q000235:genetics* / Q000276:immunology; D053078:Membrane Potential, Mitochondrial / Q000276:immunology; D008928:Mitochondria / Q000235:genetics / Q000276:immunology / Q000473:pathology / Q000821:virology*; D033681:Mitochondrial Membrane Transport Proteins / Q000235:genetics / Q000276:immunology*; D063306:Mitophagy / Q000235:genetics / Q000276:immunology; D000071199:NLR Family, Pyrin Domain-Containing 3 Protein; D017434:Protein Structure, Tertiary; D021381:Protein Transport; D011971:Receptors, Immunologic; D011994:Recombinant Proteins / Q000235:genetics / Q000276:immunology; D015398:Signal Transduction; D019076:Transgenes; D014764:Viral Proteins / Q000235:genetics / Q000276:immunology*; D000090622:Mitochondrial Precursor Protein Import Complex Proteins
chemical_list: D002352:Carrier Proteins; D000071457:DEAD Box Protein 58; D053487:DEAD-box RNA Helicases; D058847:Inflammasomes; D033681:Mitochondrial Membrane Transport Proteins; D000071199:NLR Family, Pyrin Domain-Containing 3 Protein; D011971:Receptors, Immunologic; D011994:Recombinant Proteins; D014764:Viral Proteins; C453881:NLRP3 protein, human; C442816:PB1-F2 protein, Influenza A virus; C452820:RIGI protein, human; C400783:TOMM40 protein, human; D000090622:Mitochondrial Precursor Protein Import Complex Proteins