Caspase-8-mediated cleavage inhibits IRF-3 protein by facilitating its proteasome-mediated degradation |
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Authors: | Sears Nathaniel Sen Ganes C Stark George R Chattopadhyay Saurabh |
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Institution: | Department of Molecular Genetics, Lerner Research Institute, Cleveland Clinic, Cleveland, Ohio 44195, USA. |
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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. |
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Keywords: | Caspase Double-stranded RNA Proteasome Protein Degradation Ubiquitination Caspase-8 IRF-3 Proteasomal Degradation RIG-I |
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