The adaptor protein MITA links virus-sensing receptors to IRF3 transcription factor activation

Immunity. 2008 Oct 17;29(4):538-50. doi: 10.1016/j.immuni.2008.09.003. Epub 2008 Sep 25.

Abstract

Viral infection triggers activation of transcription factors such as NF-kappaB and IRF3, which collaborate to induce type I interferons (IFNs) and elicit innate antiviral response. Here, we identified MITA as a critical mediator of virus-triggered type I IFN signaling by expression cloning. Overexpression of MITA activated IRF3, whereas knockdown of MITA inhibited virus-triggered activation of IRF3, expression of type I IFNs, and cellular antiviral response. MITA was found to localize to the outer membrane of mitochondria and to be associated with VISA, a mitochondrial protein that acts as an adaptor in virus-triggered signaling. MITA also interacted with IRF3 and recruited the kinase TBK1 to the VISA-associated complex. MITA was phosphorylated by TBK1, which is required for MITA-mediated activation of IRF3. Our results suggest that MITA is a critical mediator of virus-triggered IRF3 activation and IFN expression and further demonstrate the importance of certain mitochondrial proteins in innate antiviral immunity.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adaptor Proteins, Signal Transducing / immunology
  • Adaptor Proteins, Signal Transducing / metabolism*
  • Amino Acid Sequence
  • Cell Line
  • Cloning, Molecular
  • DEAD Box Protein 58
  • DEAD-box RNA Helicases / metabolism
  • Humans
  • Interferon Regulatory Factor-3 / metabolism*
  • Interferon Type I / immunology
  • Interferon Type I / metabolism*
  • Intracellular Membranes / metabolism
  • Membrane Proteins / chemistry
  • Membrane Proteins / genetics
  • Membrane Proteins / metabolism*
  • Mitochondria / metabolism
  • Molecular Sequence Data
  • Phosphorylation
  • Protein-Serine-Threonine Kinases / metabolism*
  • Sendai virus / immunology*
  • Sequence Alignment
  • Signal Transduction
  • Transfection

Substances

  • Adaptor Proteins, Signal Transducing
  • IRF3 protein, human
  • Interferon Regulatory Factor-3
  • Interferon Type I
  • MAVS protein, human
  • Membrane Proteins
  • STING protein, human
  • Protein-Serine-Threonine Kinases
  • TBK1 protein, human
  • DDX58 protein, human
  • DEAD Box Protein 58
  • DEAD-box RNA Helicases