Influenza A virus protein PB1-F2 translocates into mitochondria via Tom40 channels and impairs innate immunity

Takuma Yoshizumi; Takeshi Ichinohe; Osamu Sasaki; Hidenori Otera; Shun-ichiro Kawabata; Katsuyoshi Mihara; Takumi Koshiba

doi:10.1038/ncomms5713

Influenza A virus protein PB1-F2 translocates into mitochondria via Tom40 channels and impairs innate immunity

Nat Commun. 2014 Aug 20:5:4713. doi: 10.1038/ncomms5713.

Authors

Takuma Yoshizumi¹, Takeshi Ichinohe², Osamu Sasaki¹, Hidenori Otera³, Shun-ichiro Kawabata¹, Katsuyoshi Mihara³, Takumi Koshiba¹

Affiliations

¹ Department of Biology, Faculty of Sciences, Kyushu University, 6-10-1 Hakozaki, Fukuoka 812-8581, Japan.
² 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.
³ Department of Molecular Biology, Graduate School of Medical Science, Kyushu University, Fukuoka 812-8582, Japan.

PMID: 25140902
DOI: 10.1038/ncomms5713

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.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Carrier Proteins / genetics
Carrier Proteins / immunology
Cell Line, Tumor
DEAD Box Protein 58
DEAD-box RNA Helicases / genetics
DEAD-box RNA Helicases / immunology
Gene Expression Regulation
HEK293 Cells
HeLa Cells
Host-Pathogen Interactions / immunology
Humans
Immunity, Innate*
Inflammasomes / genetics
Inflammasomes / immunology
Influenza A Virus, H1N1 Subtype / chemistry
Influenza A Virus, H1N1 Subtype / genetics*
Influenza A Virus, H1N1 Subtype / immunology
Membrane Potential, Mitochondrial / immunology
Mitochondria / genetics
Mitochondria / immunology
Mitochondria / pathology
Mitochondria / virology*
Mitochondrial Membrane Transport Proteins / genetics
Mitochondrial Membrane Transport Proteins / immunology*
Mitophagy / genetics
Mitophagy / immunology
NLR Family, Pyrin Domain-Containing 3 Protein
Protein Structure, Tertiary
Protein Transport
Receptors, Immunologic
Recombinant Proteins / genetics
Recombinant Proteins / immunology
Signal Transduction
Transgenes
Viral Proteins / genetics
Viral Proteins / immunology*

Substances

Carrier Proteins
Inflammasomes
Mitochondrial Membrane Transport Proteins
NLR Family, Pyrin Domain-Containing 3 Protein
NLRP3 protein, human
PB1-F2 protein, Influenza A virus
Receptors, Immunologic
Recombinant Proteins
Tom40 protein human
Viral Proteins
RIGI protein, human
DEAD Box Protein 58
DEAD-box RNA Helicases