Mitochondrial damage elicits a TCDD-inducible poly(ADP-ribose) polymerase-mediated antiviral response

Proc Natl Acad Sci U S A. 2017 Mar 7;114(10):2681-2686. doi: 10.1073/pnas.1621508114. Epub 2017 Feb 17.


The innate immune system senses RNA viruses by pattern recognition receptors (PRRs) and protects the host from virus infection. PRRs mediate the production of immune modulatory factors and direct the elimination of RNA viruses. Here, we show a unique PRR that mediates antiviral response. Tetrachlorodibenzo-p-dioxin (TCDD)-inducible poly(ADP ribose) polymerase (TIPARP), a Cysteine3 Histidine (CCCH)-type zinc finger-containing protein, binds to Sindbis virus (SINV) RNA via its zinc finger domain and recruits an exosome to induce viral RNA degradation. TIPARP typically localizes in the nucleus, but it accumulates in the cytoplasm after SINV infection, allowing targeting of cytoplasmic SINV RNA. Redistribution of TIPARP is induced by reactive oxygen species (ROS)-dependent oxidization of the nuclear pore that affects cytoplasmic-nuclear transport. BCL2-associated X protein (BAX) and BCL2 antagonist/killer 1 (BAK1), B-cell leukemia/lymphoma 2 (BCL2) family members, mediate mitochondrial damage to generate ROS after SINV infection. Thus, TIPARP is a viral RNA-sensing PRR that mediates antiviral responses triggered by BAX- and BAK1-dependent mitochondrial damage.

Keywords: RNA degradation; antiviral response; innate immunity; mitochondrial damage; reactive oxygen species.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Active Transport, Cell Nucleus / genetics
  • Active Transport, Cell Nucleus / immunology
  • Cytoplasm / genetics
  • Cytoplasm / immunology
  • Host-Pathogen Interactions / genetics
  • Host-Pathogen Interactions / immunology
  • Humans
  • Immunity, Innate / genetics*
  • Mitochondria / genetics
  • Mitochondria / pathology
  • Mitochondria / virology
  • Nucleoside Transport Proteins
  • Poly(ADP-ribose) Polymerases / genetics*
  • Poly(ADP-ribose) Polymerases / immunology
  • RNA Viruses / genetics*
  • RNA Viruses / immunology
  • Reactive Oxygen Species / metabolism
  • Receptors, Pattern Recognition / genetics*
  • Receptors, Pattern Recognition / immunology
  • Sindbis Virus / genetics
  • Sindbis Virus / immunology
  • Sindbis Virus / pathogenicity
  • bcl-2 Homologous Antagonist-Killer Protein / genetics
  • bcl-2 Homologous Antagonist-Killer Protein / immunology
  • bcl-2-Associated X Protein / genetics
  • bcl-2-Associated X Protein / immunology


  • BAK1 protein, human
  • BAX protein, human
  • Nucleoside Transport Proteins
  • Reactive Oxygen Species
  • Receptors, Pattern Recognition
  • TiPARP protein, human
  • bcl-2 Homologous Antagonist-Killer Protein
  • bcl-2-Associated X Protein
  • Poly(ADP-ribose) Polymerases