Foot-and-mouth disease virus infection suppresses autophagy and NF-kappa B antiviral responses via degradation of ATG5-ATG12 by 3C(pro)

文献类型： 外文期刊

第一作者： Fan, Xuxu

作者： Fan, Xuxu;Han, Shichong;Yan, Dan;Gao, Yuan;Wei, Yanquan;Liu, Xiangtao;Guo, Huichen;Sun, Shiqi;Fan, Xuxu;Han, Shichong;Yan, Dan;Gao, Yuan;Wei, Yanquan;Liu, Xiangtao;Guo, Huichen;Sun, Shiqi;Han, Shichong;Liao, Ying

作者机构：

期刊名称：CELL DEATH & DISEASE （ 影响因子：8.469； 五年影响因子：8.713 ）

ISSN： 2041-4889

年卷期： 2017 年 8 卷

页码：

收录情况： SCI

摘要： Autophagy-related protein ATG5-ATG12 is an essential complex for the autophagophore elongation in autophagy, which has been reported to be involved in foot-and-mouth disease virus (FMDV) replication. Previous reports show that ATG5-ATG12 positively or negatively regulates type I interferon (IFN-alpha/beta) pathway during virus infection. In this study, we found that FMDV infection rapidly induced LC3 lipidation and GFP-LC3 subcellular redistribution at the early infection stage in PK-15 cells. Along with infection time course to 2-5 h.p.i., the levels of LC3II and ATG5-ATG12 were gradually reduced. Further study showed that ATG5-ATG12 was degraded by viral protein 3C(pro), demonstrating that FMDV suppresses autophagy along with viral protein production. Depletion of ATG5-ATG12 by siRNA knock down significantly increased the FMDV yields, whereas overexpression of ATG5-ATG12 had the opposite effects, suggesting that degradation of ATG5-ATG12 benefits virus growth. Further experiment showed that overexpression of ATG5-ATG12 positively regulated NF-kappa B pathway during FMDV infection, marked with promotion of IKK alpha/beta phosphorylation and I kappa Ba degradation, inhibition of p65 degradation, and facilitation of p65 nuclear translocation. Meanwhile, ATG5-ATG12 also promoted the phosphorylation of TBK1 and activation of IRF3 via preventing TRAF3 degradation. The positive regulation of NF-kappa B and IRF3 pathway by ATG5-ATG12 resulted in enhanced expression of IFN-beta, chemokines/cytokines, and IFN stimulated genes, including anti-viral protein PKR. Altogether, above findings suggest that ATG5-ATG12 positively regulate antiviral NF-kappa B and IRF3 signaling during FMDV infection, thereby limiting FMDV proliferation. FMDV has evolved mechanisms to counteract the antiviral function of ATG5-ATG12, via degradation of them by viral protein 3C(pro).

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