The adaptor protein MITA links virus-sensing receptors to IRF3 transcription factor activation.
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.
Zhong
Bo
B
College of Life Sciences, Wuhan University, Wuhan 430072, China.
Yang
Yan
Y
Li
Shu
S
Wang
Yan-Yi
YY
Li
Ying
Y
Diao
Feici
F
Lei
Caoqi
C
He
Xiao
X
Zhang
Lu
L
Tien
Po
P
Shu
Hong-Bing
HB
D048868:Adaptor Proteins, Signal Transducing / Q000276:immunology / Q000378:metabolism*; D000595:Amino Acid Sequence; D002460:Cell Line; D003001:Cloning, Molecular; D000071457:DEAD Box Protein 58; D053487:DEAD-box RNA Helicases / Q000378:metabolism; D006801:Humans; D050838:Interferon Regulatory Factor-3 / Q000378:metabolism*; D007370:Interferon Type I / Q000276:immunology / Q000378:metabolism*; D007425:Intracellular Membranes / Q000378:metabolism; D008565:Membrane Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D008928:Mitochondria / Q000378:metabolism; D008969:Molecular Sequence Data; D010766:Phosphorylation; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism*; D011971:Receptors, Immunologic; D029082:Sendai virus / Q000276:immunology*; D016415:Sequence Alignment; D015398:Signal Transduction; D014162:Transfection; D000099197:STING Protein
D048868:Adaptor Proteins, Signal Transducing; D000071457:DEAD Box Protein 58; D053487:DEAD-box RNA Helicases; D050838:Interferon Regulatory Factor-3; D007370:Interferon Type I; D008565:Membrane Proteins; D017346:Protein Serine-Threonine Kinases; D011971:Receptors, Immunologic; C494232:IRF3 protein, human; C505371:MAVS protein, human; C532857:STING1 protein, human; D000099197:STING Protein; C403191:TBK1 protein, human; C452820:RIGI protein, human