Journal
IMMUNITY
Volume 34, Issue 3, Pages 340-351Publisher
CELL PRESS
DOI: 10.1016/j.immuni.2010.12.018
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Funding
- Ares Trading SA, Switzerland
- Flight Attendant Medical Research Institute (FAMRI)
- Kekst Family Center for Medical Genetics
- Shapell Family Center for Genetic Disorders Research at the Weizmann Institute of Science
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Excessive responses to pattern-recognition receptors are prevented by regulatory mechanisms that affect the amounts and activities of the downstream signaling proteins. We report that activation of the transcription factor IRF3 by the ribonucleic acid sensor RIG-I was restricted by caspase-8-mediated cleavage of the RIP1 protein, which resulted in conversion of RIP1 from a signaling enhancer to a signaling inhibitor. The proteins RIP1 and caspase-8 were recruited to the RIG-I complex after viral infection and served antagonistic regulatory roles. Conjugation of ubiquitin chains to RIP1 facilitated assembly of the RIG-I complex, resulting in enhanced phosphorylation of IRF3. However, the ubiquitination of RIP1 also rendered it susceptible to caspase-8-mediated cleavage that yielded an inhibitory RIP1 fragment. The dependence of RIP1 cleavage on the same molecular change as that facilitating RIG-I signaling allows for RIG-I signaling to be restricted in its duration without compromising its initial activation.
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