Autophagy and Innate Immunity

Abstract

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-β (IFN-β) 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-β 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]