Phosphorylation-Dependent Feedback Inhibition of RIG-I by DAPK1 Identified by Kinome-wide siRNA Screening
Language English Country United States Media print-electronic
Document type Journal Article
PubMed
28132841
DOI
10.1016/j.molcel.2016.12.021
PII: S1097-2765(16)30864-4
Knihovny.cz E-resources
- Keywords
- DAPK1, DDX58, RIG-I, antiviral response, cytokines, feedback regulation, innate immunity, interferon system, pattern recognition receptors, signal transduction,
- MeSH
- A549 Cells MeSH
- Phosphorylation MeSH
- HEK293 Cells MeSH
- Cells, Cultured MeSH
- Humans MeSH
- RNA, Small Interfering genetics MeSH
- Mice MeSH
- Death-Associated Protein Kinases metabolism MeSH
- Protein Kinases metabolism MeSH
- Receptors, Retinoic Acid metabolism MeSH
- Signal Transduction MeSH
- Feedback, Physiological MeSH
- Animals MeSH
- Check Tag
- Humans MeSH
- Mice MeSH
- Animals MeSH
- Publication type
- Journal Article MeSH
- Names of Substances
- DAPK1 protein, human MeSH Browser
- RNA, Small Interfering MeSH
- PLAAT4 protein, human MeSH Browser
- Death-Associated Protein Kinases MeSH
- Protein Kinases MeSH
- Receptors, Retinoic Acid MeSH
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.
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