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Nathaniel C. Sears, Saurabh Chattopadhyay, Ganes Sen, George Stark; Caspase-8 Mediated Cleavage of Irf-3 Is Necessary For Its Proteosomal Degradation. Invest. Ophthalmol. Vis. Sci. 2011;52(14):5361.
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Interferon regulatory factor (IRF) -3 plays a critical role in induction of cellular antiviral genes via activation of endosome-bound TLR3 or cytosolic RLH signaling. In addition to inducing antiviral genes, IRF-3 plays a critical role in inducing viral apoptosis via a transcription-independent mechanism. Apoptosis is accompanied by the activation of various caspases, including caspase-8, upon activation of RIG-I. In this study we report that caspase-8, activated during
We observed the signal-dependent formation of an IRF3 fragment in an over-expression model for IRF3, with a FLAG tag at its C-terminus, in P2.1 cells. This fragment was not formed when inhibitors of Caspase-8 were present. We then tested the degradation of endogenous IRF3 in HT1080 cells after RIG-I activation, with and without selective Caspase-8 inhibition. We next investigated IRF3 degradation in ARPE19 cells before and after ectopic expression of Caspase-8.
Our study identified that caspase-8 mediated cleavage of IRF-3 represents a necessary regulatory step towards its proteasomal degradation. Such degradation of IRF-3 is known to be essential for the attenuation of antiviral and pro-inflammatory genes. Mutation of a caspase-8 cleavage motif within IRF-3 abolished its proteolytic processing and proteasomal degradation. This mutation also prevented ubiquination of IRF-3, demonstrating that caspase-8 cleave of IRF-3 serves as a necessary initial step in the ubiquitin dependant proteolytic processing of IRF-3.
We have defined a novel role for caspase-8 in the cellular viral response. It is possible that viral dsRNA can initiate two different antiviral responses, depending on the level of caspase-8 expression. If caspase-8 is present, a type-I interferon response is initiated which is then attenuated by IRF3 degradation, followed by programmed cell death. If caspase-8 is not present, a sustained type-I interferon response is initiated, not followed by IRF3 degradation and apoptosis. This finding may explain why viral infections have a tropism for certain tissues despite the ability to infect cells ubiquitously. This knowledge could lead to improved therapies against viral infection.
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