title: S6K-STING interaction regulates cytosolic DNA-mediated activation of the transcription factor IRF3.
abstract: 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.
authors.affiliation: 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.
authors.forename: Fuan
authors.initials: F
authors.lastname: Wang
authors.affiliation: Children's Hospital of Eastern Ontario Research Institute and Department of Biochemistry, Microbiology, and Immunology, University of Ottawa, Ottawa, ON K1H 8L1, Canada.
authors.forename: Tommy
authors.initials: T
authors.lastname: Alain
authors.affiliation: Department of Medicine, Molecular Microbiology, Pathology & Immunology, Washington, University School of Medicine, St Louis, MO 63110, United States of America.
authors.forename: Kristy J
authors.initials: KJ
authors.lastname: Szretter
authors.affiliation: 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.
authors.forename: Kyle
authors.initials: K
authors.lastname: Stephenson
authors.affiliation: 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.
authors.forename: Jonathan G
authors.initials: JG
authors.lastname: Pol
authors.affiliation: 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.
authors.forename: Matthew J
authors.initials: MJ
authors.lastname: Atherton
authors.affiliation: Children's Hospital of Eastern Ontario Research Institute and Department of Biochemistry, Microbiology, and Immunology, University of Ottawa, Ottawa, ON K1H 8L1, Canada.
authors.forename: Huy-Dung
authors.initials: HD
authors.lastname: Hoang
authors.affiliation: Children's Hospital of Eastern Ontario Research Institute and Department of Biochemistry, Microbiology, and Immunology, University of Ottawa, Ottawa, ON K1H 8L1, Canada.
authors.forename: Bruno D
authors.initials: BD
authors.lastname: Fonseca
authors.affiliation: Department of Biochemistry and Goodman Cancer Research Centre, McGill University, Montreal, Quebec, Canada.
authors.forename: Chadi
authors.initials: C
authors.lastname: Zakaria
authors.affiliation: 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.
authors.forename: Lan
authors.initials: L
authors.lastname: Chen
authors.affiliation: 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.
authors.forename: Zainab
authors.initials: Z
authors.lastname: Rangwala
authors.affiliation: 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.
authors.forename: Adam
authors.initials: A
authors.lastname: Hesch
authors.affiliation: 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.
authors.forename: Eva Sin Yan
authors.initials: ESY
authors.lastname: Chan
authors.affiliation: 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.
authors.forename: Carly
authors.initials: C
authors.lastname: Tuinman
authors.affiliation: Department of Pediatrics, Emory Vaccine Center, Emory University, Atlanta, GA 30329, United States of America.
authors.forename: Mehul S
authors.initials: MS
authors.lastname: Suthar
authors.affiliation: Division of Infectious Diseases and Immunology, Department of Medicine, University of Massachusetts Medical School, Worcester, MA 01605, United States of America.
authors.forename: Zhaozhao
authors.initials: Z
authors.lastname: Jiang
authors.affiliation: 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.
authors.forename: Ali A
authors.initials: AA
authors.lastname: Ashkar
authors.affiliation: 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.
authors.forename: George
authors.initials: G
authors.lastname: Thomas
authors.affiliation: 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.
authors.forename: Sara C
authors.initials: SC
authors.lastname: Kozma
authors.affiliation: Department of Immunology, University of Washington School of Medicine, Seattle, Washington, WA98195, United States of America.
authors.forename: Michael
authors.initials: M
authors.lastname: Gale
authors.affiliation: Division of Infectious Diseases and Immunology, Department of Medicine, University of Massachusetts Medical School, Worcester, MA 01605, United States of America.
authors.forename: Katherine A
authors.initials: KA
authors.lastname: Fitzgerald
authors.affiliation: Department of Medicine, Molecular Microbiology, Pathology & Immunology, Washington, University School of Medicine, St Louis, MO 63110, United States of America.
authors.forename: Michael S
authors.initials: MS
authors.lastname: Diamond
authors.affiliation: 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.
authors.forename: Karen
authors.initials: K
authors.lastname: Mossman
authors.affiliation: Department of Biochemistry and Goodman Cancer Research Centre, McGill University, Montreal, Quebec, Canada.
authors.forename: Nahum
authors.initials: N
authors.lastname: Sonenberg
authors.affiliation: 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.
authors.forename: Yonghong
authors.initials: Y
authors.lastname: Wan
authors.affiliation: 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.
authors.forename: Brian D
authors.initials: BD
authors.lastname: Lichty
mesh_terms: D000256:Adenoviridae / Q000235:genetics / Q000276:immunology; D000818:Animals; D001854:Bone Marrow Cells / Q000276:immunology / Q000378:metabolism; D002478:Cells, Cultured; D003600:Cytosol / Q000276:immunology / Q000378:metabolism / Q000821:virology; D004247:DNA / Q000235:genetics / Q000276:immunology* / Q000378:metabolism; D003713:Dendritic Cells / Q000276:immunology / Q000378:metabolism; D057809:HEK293 Cells; D006561:Herpes Simplex / Q000276:immunology / Q000821:virology; D018259:Herpesvirus 1, Human / Q000276:immunology / Q000502:physiology; D006801:Humans; D007114:Immunization / Q000379:methods; D015151:Immunoblotting; D050838:Interferon Regulatory Factor-3 / Q000235:genetics / Q000276:immunology* / Q000378:metabolism; D008565:Membrane Proteins / Q000235:genetics / Q000276:immunology* / Q000378:metabolism; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009713:Nucleotidyltransferases / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D010047:Ovalbumin / Q000235:genetics / Q000276:immunology; D011485:Protein Binding; D017346:Protein Serine-Threonine Kinases / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D038744:Ribosomal Protein S6 Kinases, 90-kDa / Q000235:genetics / Q000276:immunology* / Q000378:metabolism; D000099197:STING Protein; D000099235:Cyclic Guanosine Monophosphate-Adenosine Monophosphate Synthase
chemical_list: D004247:DNA; D050838:Interferon Regulatory Factor-3; D008565:Membrane Proteins; D009713:Nucleotidyltransferases; D010047:Ovalbumin; D017346:Protein Serine-Threonine Kinases; D038744:Ribosomal Protein S6 Kinases, 90-kDa; C494233:Irf3 protein, mouse; C530855:Sting1 protein, mouse; D000099197:STING Protein; C498588:Tbk1 protein, mouse; C512964:Rps6ka1 protein, mouse; C578391:cGAS protein, mouse; D000099235:Cyclic Guanosine Monophosphate-Adenosine Monophosphate Synthase