title: Phosphorylation-Dependent Feedback Inhibition of RIG-I by DAPK1 Identified by Kinome-wide siRNA Screening.
abstract: Cell-autonomous induction of type I interferon must be stringently regulated. Rapid induction is key to control virus infection, whereas proper limitation of signaling is essential to prevent immunopathology and autoimmune disease. Using unbiased kinome-wide RNAi screening followed by thorough validation, we identified 22 factors that regulate RIG-I/IRF3 signaling activity. We describe a negative-feedback mechanism targeting RIG-I activity, which is mediated by death associated protein kinase 1 (DAPK1). RIG-I signaling triggers DAPK1 kinase activation, and active DAPK1 potently inhibits RIG-I stimulated IRF3 activity and interferon-beta production. DAPK1 phosphorylates RIG-I in vitro at previously reported as well as other sites that limit 5'ppp-dsRNA sensing and virtually abrogate RIG-I activation.
authors.affiliation: Research Group "Dynamics of early viral infection and the innate antiviral response," Division Virus-associated carcinogenesis (F170), German Cancer Research Center (DKFZ), 69120 Heidelberg, Germany; Department for Infectious Diseases, Molecular Virology, Research Group "Dynamics of early viral infection and the innate antiviral response," Medical Faculty, Heidelberg University, 69120 Heidelberg, Germany.
authors.forename: Joschka
authors.initials: J
authors.lastname: Willemsen
authors.affiliation: Department for Infectious Diseases, Molecular Virology, Research Group "Dynamics of early viral infection and the innate antiviral response," Medical Faculty, Heidelberg University, 69120 Heidelberg, Germany.
authors.forename: Oliver
authors.initials: O
authors.lastname: Wicht
authors.affiliation: Research Group "Dynamics of early viral infection and the innate antiviral response," Division Virus-associated carcinogenesis (F170), German Cancer Research Center (DKFZ), 69120 Heidelberg, Germany.
authors.forename: Julia C
authors.initials: JC
authors.lastname: Wolanski
authors.affiliation: Department for Infectious Diseases, Molecular Virology, Research Group "Dynamics of early viral infection and the innate antiviral response," Medical Faculty, Heidelberg University, 69120 Heidelberg, Germany.
authors.forename: Nina
authors.initials: N
authors.lastname: Baur
authors.affiliation: Research Group "Dynamics of early viral infection and the innate antiviral response," Division Virus-associated carcinogenesis (F170), German Cancer Research Center (DKFZ), 69120 Heidelberg, Germany.
authors.forename: Sandra
authors.initials: S
authors.lastname: Bastian
authors.affiliation: Innate Immunity Laboratory, Max-Planck Institute of Biochemistry, Am Klopferspitz 18, 82152 Martinsried, Germany.
authors.forename: Darya A
authors.initials: DA
authors.lastname: Haas
authors.affiliation: Biomedical Computer Vision Group, BioQuant, IPMB, and German Cancer Research Center (DKFZ), Department of Bioinformatics and Functional Genomics, Heidelberg University, 69120 Heidelberg, Germany; Center for Biomedical Image Analysis, Faculty of Informatics, Masaryk University, 60200 Brno, Czech Republic.
authors.forename: Petr
authors.initials: P
authors.lastname: Matula
authors.affiliation: ViroQuant Research Group Modeling, BioQuant, Heidelberg University, 69120 Heidelberg, Germany.
authors.forename: Bettina
authors.initials: B
authors.lastname: Knapp
authors.affiliation: ENYO Pharma, 69007 Lyon, France.
authors.forename: Laurène
authors.initials: L
authors.lastname: Meyniel-Schicklin
authors.affiliation: Center for Advanced Biotechnology and Medicine, Department of Chemistry and Chemical Biology, Rutgers University, Piscataway, NJ 08854, USA.
authors.forename: Chen
authors.initials: C
authors.lastname: Wang
authors.affiliation: Department for Infectious Diseases, Molecular Virology, Medical Faculty, Heidelberg University, 69120 Heidelberg, Germany.
authors.forename: Ralf
authors.initials: R
authors.lastname: Bartenschlager
authors.affiliation: Department for Infectious Diseases, Molecular Virology, Medical Faculty, Heidelberg University, 69120 Heidelberg, Germany.
authors.forename: Volker
authors.initials: V
authors.lastname: Lohmann
authors.affiliation: Biomedical Computer Vision Group, BioQuant, IPMB, and German Cancer Research Center (DKFZ), Department of Bioinformatics and Functional Genomics, Heidelberg University, 69120 Heidelberg, Germany.
authors.forename: Karl
authors.initials: K
authors.lastname: Rohr
authors.affiliation: ViroQuant-CellNetworks RNAi Screening Facility, BioQuant, Heidelberg University, 69120 Heidelberg, Germany.
authors.forename: Holger
authors.initials: H
authors.lastname: Erfle
authors.affiliation: ViroQuant Research Group Modeling, BioQuant, Heidelberg University, 69120 Heidelberg, Germany; Institute for Bioinformatics, University Medicine Greifswald, 17475 Greifswald, Germany.
authors.forename: Lars
authors.initials: L
authors.lastname: Kaderali
authors.affiliation: Center for Advanced Biotechnology and Medicine, Department of Chemistry and Chemical Biology, Rutgers University, Piscataway, NJ 08854, USA.
authors.forename: Joseph
authors.initials: J
authors.lastname: Marcotrigiano
authors.affiliation: Innate Immunity Laboratory, Max-Planck Institute of Biochemistry, Am Klopferspitz 18, 82152 Martinsried, Germany.
authors.forename: Andreas
authors.initials: A
authors.lastname: Pichlmair
authors.affiliation: Research Group "Dynamics of early viral infection and the innate antiviral response," Division Virus-associated carcinogenesis (F170), German Cancer Research Center (DKFZ), 69120 Heidelberg, Germany; Department for Infectious Diseases, Molecular Virology, Research Group "Dynamics of early viral infection and the innate antiviral response," Medical Faculty, Heidelberg University, 69120 Heidelberg, Germany. Electronic address: m.binder@dkfz.de.
authors.forename: Marco
authors.initials: M
authors.lastname: Binder
mesh_terms: D000072283:A549 Cells; D000818:Animals; D002478:Cells, Cultured; D064550:Death-Associated Protein Kinases / Q000378:metabolism*; D025461:Feedback, Physiological; D057809:HEK293 Cells; D006801:Humans; D051379:Mice; D010766:Phosphorylation; D011494:Protein Kinases / Q000378:metabolism; D034741:RNA, Small Interfering / Q000235:genetics*; D018168:Receptors, Retinoic Acid / Q000378:metabolism*; D015398:Signal Transduction
chemical_list: C437968:PLAAT4 protein, human; D034741:RNA, Small Interfering; D018168:Receptors, Retinoic Acid; D011494:Protein Kinases; C579096:DAPK1 protein, human; D064550:Death-Associated Protein Kinases
keywords: DAPK1; DDX58; RIG-I; antiviral response; cytokines; feedback regulation; innate immunity; interferon system; pattern recognition receptors; signal transduction