Bax-dependent mitochondrial membrane permeabilization enhances IRF3-mediated innate immune response during VSV infection |
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Authors: | Sharif-Askari Ehssan Nakhaei Peyman Oliere Stephanie Tumilasci Vanessa Hernandez Eduardo Wilkinson Peter Lin Rongtuan Bell John Hiscott John |
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Institution: | Molecular Oncology Group, Lady Davis Institute, Jewish General Hospital, McGill University, Montreal, Quebec, Canada. |
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Abstract: | An effective type I interferon (IFN-alpha/beta) response is critical for the control of many viral infections. Using an oncolytic strain of vesicular stomatitis virus, we have examined the cross-talk between virus-induced apoptosis and initiation of innate immune response. The intrinsic apoptotic cascade, specifically the Bax-Bcl-2-Caspase-9 cascade, was revealed as the primary pathway of VSV-induced apoptosis. Cell death was significantly reduced in BaxBak(-/-) murine embryonic fibroblasts (MEFs) and in human A549 epithelial cells treated with siRNA against Bax. Although inhibition of apoptosis resulted in enhanced virus replication in the BaxBak(-/-) MEFs as compared to wild-type cells, induction of the IFN antiviral response and expression of cytokine genes were attenuated in virus-infected cells. Moreover, Bax but not Bak pro-apoptotic protein was required for IRF-3 phosphorylation and activation, further substantiating a role for the intrinsic mitochondrial pathway in the innate immune response. Therefore, virus-induced apoptosis through a Bax-dependent mitochondrial pathway appears to enhance the full development of the IRF-3 mediated IFN antiviral response. |
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Keywords: | Mitochondria IRF-3 Innate immunity VSV Bax |
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