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Nat Immunol. 2016 May;17(5):514-522. doi: 10.1038/ni.3433. Epub 2016 Apr 4.

S6K-STING interaction regulates cytosolic DNA-mediated activation of the transcription factor IRF3.

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McMaster Immunology Research Centre, Department of Pathology and Molecular Medicine, McMaster University, Hamilton, Ontario, Canada.
MG DeGroote Institute for Infectious Disease Research, McMaster University, Hamilton, Ontario, Canada.
Children's Hospital of Eastern Ontario Research Institute and Department of Biochemistry, Microbiology, and Immunology, University of Ottawa, Ottawa, ON K1H 8L1, Canada.
Department of Medicine, Molecular Microbiology, Pathology & Immunology, Washington, University School of Medicine, St Louis, MO 63110, United States of America.
Department of Biochemistry and Goodman Cancer Research Centre, McGill University, Montreal, Quebec, Canada.
Department of Pediatrics, Emory Vaccine Center, Emory University, Atlanta, GA 30329, United States of America.
Division of Infectious Diseases and Immunology, Department of Medicine, University of Massachusetts Medical School, Worcester, MA 01605, United States of America.
Department of of Internal Medicine, Division of Hematology/Oncology, University of Cincinnati Medical School, Cincinnati, 45267-0508 OH, United States of America.
Laboratory of Metabolism and Cancer, Catalan Institute of Oncology, ICO, Bellvitge Biomedical Research Institute, IDIBELL, 08908 Barcelona, Spain.
Departament Ciències Fisiològiques II, Facultat de Medicina, Universitat de Barcelona, 08908, Barcelona, Spain.
Department of Immunology, University of Washington School of Medicine, Seattle, Washington, WA98195, United States of America.
Contributed equally


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.

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