title: Caspase-8-mediated cleavage inhibits IRF-3 protein by facilitating its proteasome-mediated degradation.
abstract: Interferon regulatory factor 3 (IRF-3) plays a central role in inducing the expression of cellular antiviral genes, including the interferon-β gene, in response to Pattern Recognition Receptors. IRF-3 is targeted for proteasome-mediated degradation, which modulates the strength and duration of the innate immune responses that depend on it. We have found that caspase-8, which is activated by cytosolic RIG-I-dependent signaling, catalyzes an essential intermediate step in the ubiquitination and proteasome-mediated degradation of IRF-3. Mutation of a consensus cleavage site within IRF-3 generates a form that is not cleaved by caspase-8 and that is protected from ubiquitination and degradation. An in vitro assay confirms the direct action of caspase-8 cleavage on IRF-3. We also show that caspase-8-mediated cleavage of IRF-3 helps to modulate dsRNA-dependent gene induction.
authors.affiliation: Department of Molecular Genetics, Lerner Research Institute, Cleveland Clinic, Cleveland, Ohio 44195, USA.
authors.forename: Nathaniel
authors.initials: N
authors.lastname: Sears
authors.forename: Ganes C
authors.initials: GC
authors.lastname: Sen
authors.forename: George R
authors.initials: GR
authors.lastname: Stark
authors.forename: Saurabh
authors.initials: S
authors.lastname: Chattopadhyay
mesh_terms: D053181:Caspase 8 / Q000378:metabolism*; D045744:Cell Line, Tumor; D004789:Enzyme Activation; D005786:Gene Expression Regulation; D006801:Humans; D050838:Interferon Regulatory Factor-3 / Q000378:metabolism*; D008954:Models, Biological; D050505:Mutant Proteins / Q000378:metabolism; D009154:Mutation / Q000235:genetics; D046988:Proteasome Endopeptidase Complex / Q000378:metabolism*; D011499:Protein Processing, Post-Translational; D020365:RNA Helicases / Q000378:metabolism; D012330:RNA, Double-Stranded / Q000378:metabolism; D029082:Sendai virus / Q000378:metabolism; D015398:Signal Transduction; D054875:Ubiquitination
chemical_list: C494232:IRF3 protein, human; D050838:Interferon Regulatory Factor-3; D050505:Mutant Proteins; D012330:RNA, Double-Stranded; C505530:CASP8 protein, human; D053181:Caspase 8; D046988:Proteasome Endopeptidase Complex; D020365:RNA Helicases