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.

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
  • 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
  • Recombinant Proteins
  • Tom40 protein human
  • Viral Proteins
  • DDX58 protein, human
  • DEAD Box Protein 58
  • DEAD-box RNA Helicases