RIG-I RNA helicase activation of irf3 transcription factor is negatively regulated by caspase-8-mediated cleavage of the RIP1 protein

Akhil Rajput, Andrew Kovalenko, Konstantin Bogdanov, Seung Hoon Yang, Tae Bong Kang, Jin Chul Kim, Jianfang Du, David Wallach

Research output: Contribution to journalArticlepeer-review

178 Scopus citations

Abstract

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.

Original languageEnglish
Pages (from-to)340-351
Number of pages12
JournalImmunity
Volume34
Issue number3
DOIs
StatePublished - 25 Mar 2011

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