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.
Original language | English |
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Pages (from-to) | 403-415.e8 |
Journal | Molecular Cell |
Volume | 65 |
Issue number | 3 |
DOIs | |
State | Published - 2 Feb 2017 |
Externally published | Yes |
Keywords
- DAPK1
- DDX58
- RIG-I
- antiviral response
- cytokines
- feedback regulation
- innate immunity
- interferon system
- pattern recognition receptors
- signal transduction