Journal
MOLECULAR CELL
Volume 65, Issue 3, Pages 403-+Publisher
CELL PRESS
DOI: 10.1016/j.molcel.2016.12.021
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Funding
- DFG [BI1693/1-1, TRR179]
- Medical Faculty Heidelberg Postdoc Fellowship
- BMBF e: Bio ImmunoQuant
- BMBF FORSYS ViroQuant
- EU FP7 SysPatho
- CellNetworks - Cluster of Excellence [EXC81]
- [GBP302/12/G157]
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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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