Sci. STKE, 4 September 2007
Autophagy Autophagy and Innate Immunity
John F. Foley
Sciences STKE, AAAS, Washington, DC 20005, USA
The cytoplasmic contents of the cell are targeted to lysosomes for degradation or recycling by a process known as autophagy. Jounai et al. investigated the role of autophagy in the response to infection by vesicular stomatitis virus (VSV). Whereas mouse embryonic fibroblasts (MEFs) from wild-type mice were efficiently infected with VSV, as assessed by measurement of virus in infected cell cultures, MEFs from mice deficient in Atg5 (Atg5 KO), a critical component of the autophagic process, produced much lower amounts of virus. Real-time reverse transcription polymerase chain reaction and Western blotting analyses demonstrated that VSV infection of Atg5 KO MEFs resulted in the higher abundance of interferon- (IFN-) mRNA and increased phosphorylation and activation of interferon regulatory factor 3 (IRF-3), a transcription factor that activates IFN gene expression, than did infection of wild-type MEFs. Viral RNA is recognized by DExD/H box RNA helicases, such as retinoic acid-inducible gene I (RIG-I), which then associates with and activates the adaptor molecule IFN- promoter stimulator 1 (IPS-1). This association is mediated by interactions between the caspase recruitment domains (CARDs) of RIG-I and IPS-1 and leads to IRF-3 activation. Reporter assays in 293 cells demonstrated that RIG-1-induced activation of the IFN promoter was inhibited by both Agt5 and a conjugate of Agt5 and Agt12 (the physiologically relevant form of Atg5). Atg5-Atg12 coimmunoprecipitated with RIG-I and IPS-1 in 293 cells, and VSV infection enhanced the association between Atg5-Atg12 and IPS-1. Experiments with mutant forms of IPS-1 and RIG-I showed that the CARD domains were the targets of Atg5-Atg12. This study suggests that Atg5-Atg12 blocks the interaction between RIG-I and IPS-1 and thus inhibits the innate immune response to viral infection.
N. Jounai, F. Takeshita, K. Kobiyama, A. Sawano, A. Miyawaki, K.-Q. Xin, K. J. Ishii, T. Kawai, S. Akira, K. Suzuki, K. Okuda, The Atg5-Atg12 conjugate associates with innate antiviral immune responses. Proc. Natl. Acad. Sci. U.S.A. 104, 14050-14055 (2007). [Abstract] [Full Text]
Citation: J. F. Foley, Autophagy and Innate Immunity. Sci. STKE 2007, tw318 (2007).
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