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Mol Cell. 2017 Feb 2;65(3):403-415.e8. doi: 10.1016/j.molcel.2016.12.021. Epub 2017 Jan 26.

Phosphorylation-Dependent Feedback Inhibition of RIG-I by DAPK1 Identified by Kinome-wide siRNA Screening.

Author information

1
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.
2
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.
3
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.
4
Innate Immunity Laboratory, Max-Planck Institute of Biochemistry, Am Klopferspitz 18, 82152 Martinsried, Germany.
5
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.
6
ViroQuant Research Group Modeling, BioQuant, Heidelberg University, 69120 Heidelberg, Germany.
7
ENYO Pharma, 69007 Lyon, France.
8
Center for Advanced Biotechnology and Medicine, Department of Chemistry and Chemical Biology, Rutgers University, Piscataway, NJ 08854, USA.
9
Department for Infectious Diseases, Molecular Virology, Medical Faculty, Heidelberg University, 69120 Heidelberg, Germany.
10
Biomedical Computer Vision Group, BioQuant, IPMB, and German Cancer Research Center (DKFZ), Department of Bioinformatics and Functional Genomics, Heidelberg University, 69120 Heidelberg, Germany.
11
ViroQuant-CellNetworks RNAi Screening Facility, BioQuant, Heidelberg University, 69120 Heidelberg, Germany.
12
ViroQuant Research Group Modeling, BioQuant, Heidelberg University, 69120 Heidelberg, Germany; Institute for Bioinformatics, University Medicine Greifswald, 17475 Greifswald, Germany.
13
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.

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.

KEYWORDS:

DAPK1; DDX58; RIG-I; antiviral response; cytokines; feedback regulation; innate immunity; interferon system; pattern recognition receptors; signal transduction

PMID:
28132841
DOI:
10.1016/j.molcel.2016.12.021
[Indexed for MEDLINE]
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