title: Foot-and-mouth disease virus infection suppresses autophagy and NF-кB antiviral responses via degradation of ATG5-ATG12 by 3Cpro.
abstract: 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-α/β) 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 3Cpro, 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-кB pathway during FMDV infection, marked with promotion of IKKα/β phosphorylation and IκBα 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-кB and IRF3 pathway by ATG5-ATG12 resulted in enhanced expression of IFN-β, chemokines/cytokines, and IFN stimulated genes, including anti-viral protein PKR. Altogether, above findings suggest that ATG5-ATG12 positively regulate anti-viral NF-κB 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 3Cpro.
authors.affiliation: State Key Laboratory of Veterinary Etiological Biology and National Foot and Mouth Disease Reference Laboratory, Lanzhou Veterinary Research Institute, Chinese Academy of Agricultural Sciences, Lanzhou, Gansu, P. R. China.
authors.forename: Xuxu
authors.initials: X
authors.lastname: Fan
authors.affiliation: State Key Laboratory of Veterinary Etiological Biology and National Foot and Mouth Disease Reference Laboratory, Lanzhou Veterinary Research Institute, Chinese Academy of Agricultural Sciences, Lanzhou, Gansu, P. R. China.|Key Laboratory of Zoonosis of Ministry of Agriculture, College of Veterinary Medicine, China Agricultural University, Haidian District, Beijing, P. R. China.
authors.forename: Shichong
authors.initials: S
authors.lastname: Han
authors.affiliation: State Key Laboratory of Veterinary Etiological Biology and National Foot and Mouth Disease Reference Laboratory, Lanzhou Veterinary Research Institute, Chinese Academy of Agricultural Sciences, Lanzhou, Gansu, P. R. China.
authors.forename: Dan
authors.initials: D
authors.lastname: Yan
authors.affiliation: State Key Laboratory of Veterinary Etiological Biology and National Foot and Mouth Disease Reference Laboratory, Lanzhou Veterinary Research Institute, Chinese Academy of Agricultural Sciences, Lanzhou, Gansu, P. R. China.
authors.forename: Yuan
authors.identifier: 0000-0002-6149-5487
authors.initials: Y
authors.lastname: Gao
authors.affiliation: State Key Laboratory of Veterinary Etiological Biology and National Foot and Mouth Disease Reference Laboratory, Lanzhou Veterinary Research Institute, Chinese Academy of Agricultural Sciences, Lanzhou, Gansu, P. R. China.
authors.forename: Yanquan
authors.initials: Y
authors.lastname: Wei
authors.affiliation: State Key Laboratory of Veterinary Etiological Biology and National Foot and Mouth Disease Reference Laboratory, Lanzhou Veterinary Research Institute, Chinese Academy of Agricultural Sciences, Lanzhou, Gansu, P. R. China.
authors.forename: Xiangtao
authors.initials: X
authors.lastname: Liu
authors.affiliation: Department of Avian Diseases, Shanghai Veterinary Research Institute, Chinese Academy of Agricultural Sciences, Shanghai, P. R. China.
authors.forename: Ying
authors.initials: Y
authors.lastname: Liao
authors.affiliation: State Key Laboratory of Veterinary Etiological Biology and National Foot and Mouth Disease Reference Laboratory, Lanzhou Veterinary Research Institute, Chinese Academy of Agricultural Sciences, Lanzhou, Gansu, P. R. China.
authors.forename: Huichen
authors.initials: H
authors.lastname: Guo
authors.affiliation: State Key Laboratory of Veterinary Etiological Biology and National Foot and Mouth Disease Reference Laboratory, Lanzhou Veterinary Research Institute, Chinese Academy of Agricultural Sciences, Lanzhou, Gansu, P. R. China.
authors.forename: Shiqi
authors.initials: S
authors.lastname: Sun
mesh_terms: D000086042:3C Viral Proteases; D000818:Animals; D001343:Autophagy / Q000235:genetics; D000071192:Autophagy-Related Protein 12 / Q000235:genetics / Q000378:metabolism*; D000071187:Autophagy-Related Protein 5 / Q000235:genetics / Q000378:metabolism*; D003546:Cysteine Endopeptidases / Q000096:biosynthesis / Q000235:genetics*; D005536:Foot-and-Mouth Disease / Q000235:genetics* / Q000473:pathology / Q000821:virology; D029544:Foot-and-Mouth Disease Virus / Q000235:genetics* / Q000254:growth & development / Q000472:pathogenicity; D015967:Gene Expression Regulation, Viral; D050838:Interferon Regulatory Factor-3 / Q000235:genetics* / Q000378:metabolism; D016328:NF-kappa B / Q000235:genetics; D011485:Protein Binding; D017346:Protein Serine-Threonine Kinases / Q000235:genetics; D034741:RNA, Small Interfering / Q000235:genetics; D015398:Signal Transduction; D014764:Viral Proteins / Q000096:biosynthesis / Q000235:genetics*; D014779:Virus Replication
chemical_list: C466624:ATG12 protein, human; C502778:ATG5 protein, human; D000071192:Autophagy-Related Protein 12; D000071187:Autophagy-Related Protein 5; C494232:IRF3 protein, human; D050838:Interferon Regulatory Factor-3; D016328:NF-kappa B; D034741:RNA, Small Interfering; D014764:Viral Proteins; D017346:Protein Serine-Threonine Kinases; C403191:TBK1 protein, human; D003546:Cysteine Endopeptidases; D000086042:3C Viral Proteases