학술논문
S6K-STING interaction regulates cytosolic DNA-mediated activation of the transcription factor IRF3
Document Type
Report
Author
Wang, Fuan; Alain, Tommy; Szretter, Kristy J.; Stephenson, Kyle; Pol, Jonathan G.; Atherton, Matthew J.; Hoang, Huy- Dung; Fonseca, Bruno D.; Zakaria, Chadi; Chen, Lan; Rangwala, Zainab; Hesch, Adam; Chan, Eva Sin Yan; Tuinman, Carly; Suthar, Mehul S.; Jiang, Zhaozhao; Ashkar, Ali A.; Thomas, George; Kozma, Sara C.; Gale, Jr., Michael; Fitzgerald, Katherine A.; Diamond, Michael S.; Mossman, Karen; Sonenberg, Nahum; Wan, Yonghong; Lichty, Brian D.
Source
Nature Immunology. May 1, 2016, p514, 11 p.
Subject
Language
English
ISSN
1529-2908
Abstract
In eukaryotic cells, double-stranded DNA is normally sequestered in the nucleus or the mitochondria and is thereby prevented from direct contact with the cytosol. Thus, cytosolic exposure of DNA resulting [...]
Cytosolic DNA-mediated activation of the transcription factor IRF3 is a key event in host antiviral responses. Here we found that infection with DNA viruses induced interaction of the metabolic checkpoint kinase mTOR downstream effector and kinase S6K1 and the signaling adaptor STING in a manner dependent on the DNA sensor cGAS. We further demonstrated that the kinase domain, but not the kinase function, of S6K1 was required for the S6K1-STING interaction and that the TBK1 critically promoted this process. The formation of a tripartite S6K1-STING-TBK1 complex was necessary for the activation of IRF3, and disruption of this signaling axis impaired the early-phase expression of IRF3 target genes and the induction of T cell responses and mucosal antiviral immunity. Thus, our results have uncovered a fundamental regulatory mechanism for the activation of IRF3 in the cytosolic DNA pathway.
Cytosolic DNA-mediated activation of the transcription factor IRF3 is a key event in host antiviral responses. Here we found that infection with DNA viruses induced interaction of the metabolic checkpoint kinase mTOR downstream effector and kinase S6K1 and the signaling adaptor STING in a manner dependent on the DNA sensor cGAS. We further demonstrated that the kinase domain, but not the kinase function, of S6K1 was required for the S6K1-STING interaction and that the TBK1 critically promoted this process. The formation of a tripartite S6K1-STING-TBK1 complex was necessary for the activation of IRF3, and disruption of this signaling axis impaired the early-phase expression of IRF3 target genes and the induction of T cell responses and mucosal antiviral immunity. Thus, our results have uncovered a fundamental regulatory mechanism for the activation of IRF3 in the cytosolic DNA pathway.