title: RIG-I RNA helicase activation of IRF3 transcription factor is negatively regulated by caspase-8-mediated cleavage of the RIP1 protein.
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.
authors.affiliation: Department of Biological Chemistry, The Weizmann Institute of Science, 76100 Rehovot, Israel.
authors.forename: Akhil
authors.initials: A
authors.lastname: Rajput
authors.forename: Andrew
authors.initials: A
authors.lastname: Kovalenko
authors.forename: Konstantin
authors.initials: K
authors.lastname: Bogdanov
authors.forename: Seung-Hoon
authors.initials: SH
authors.lastname: Yang
authors.forename: Tae-Bong
authors.initials: TB
authors.lastname: Kang
authors.forename: Jin-Chul
authors.initials: JC
authors.lastname: Kim
authors.forename: Jianfang
authors.initials: J
authors.lastname: Du
authors.forename: David
authors.initials: D
authors.lastname: Wallach
mesh_terms: D000818:Animals; D053181:Caspase 8 / Q000235:genetics / Q000276:immunology*; D045744:Cell Line, Tumor; D005786:Gene Expression Regulation; D055785:Gene Knockdown Techniques; D057809:HEK293 Cells; D006367:HeLa Cells; D006801:Humans; D015151:Immunoblotting; D050838:Interferon Regulatory Factor-3 / Q000276:immunology*; D051379:Mice; D046228:Microarray Analysis; D028861:Nuclear Pore Complex Proteins / Q000276:immunology*; D020365:RNA Helicases / Q000276:immunology* / Q000378:metabolism; D016601:RNA-Binding Proteins / Q000276:immunology*; D018168:Receptors, Retinoic Acid / Q000276:immunology*; D012097:Repressor Proteins / Q000276:immunology; D020133:Reverse Transcriptase Polymerase Chain Reaction
chemical_list: C119724:AGFG1 protein, human; D050838:Interferon Regulatory Factor-3; D028861:Nuclear Pore Complex Proteins; C437968:PLAAT4 protein, human; D016601:RNA-Binding Proteins; D018168:Receptors, Retinoic Acid; D012097:Repressor Proteins; D053181:Caspase 8; D020365:RNA Helicases