title: Foot-and-Mouth Disease Virus Viroporin 2B Antagonizes RIG-I-Mediated Antiviral Effects by Inhibition of Its Protein Expression.
abstract: The role of retinoic acid-inducible gene I (RIG-I) in foot-and-mouth disease virus (FMDV)-infected cells remains unknown. Here, we showed that RIG-I inhibits FMDV replication in host cells. FMDV infection increased the transcription of RIG-I, while it decreased RIG-I protein expression. A detailed analysis revealed that FMDV leader proteinase (Lpro), as well as 3C proteinase (3Cpro) and 2B protein, decreased RIG-I protein expression. Lproand 3Cproare viral proteinases that can cleave various host proteins and are responsible for several of the viral polyprotein cleavages. However, for the first time, we observed 2B-induced reduction of host protein. Further studies showed that 2B-mediated reduction of RIG-I is specific to FMDV, but not other picornaviruses, including encephalomyocarditis virus, enterovirus 71, and coxsackievirus A16. Moreover, we found the decreased protein level of RIG-I is independent of the cleavage of eukaryotic translation initiation factor 4 gamma, the induction of cellular apoptosis, or the association of proteasome, lysosome, and caspase pathways. A direct interaction was observed between RIG-I and 2B. The carboxyl-terminal amino acids 105 to 114 and amino acids 135 to 144 of 2B were essential for the reduction of RIG-I, while residues 105 to 114 were required for the interaction. These data suggest the antiviral role of RIG-I against FMDV and a novel antagonistic mechanism of FMDV that is mediated by 2B protein.
  
  
  OBJECTIVE
  This study demonstrated that RIG-I could suppress FMDV replication during virus infection. FMDV infection increased the transcriptional expression of RIG-I, while it decreased RIG-I protein expression. FMDV 2B protein interacted with RIG-I and induced reduction of RIG-I. 2B-induced reduction of RIG-I was independent of the induction of the cleavage of eukaryotic translation initiation factor 4 gamma or cellular apoptosis. In addition, proteasome, lysosome, and caspase pathways were not involved in this process. This study provides new insight into the immune evasion mediated by FMDV and identifies 2B as an antagonistic factor for FMDV to evade the antiviral response.
authors.affiliation: State Key Laboratory of Veterinary Etiological Biology, National Foot and Mouth Diseases Reference Laboratory, Key Laboratory of Animal Virology of Ministry of Agriculture, Lanzhou Veterinary Research Institute, Chinese Academy of Agricultural Sciences, Lanzhou, China.
authors.forename: Zixiang
authors.initials: Z
authors.lastname: Zhu
authors.affiliation: State Key Laboratory of Veterinary Etiological Biology, National Foot and Mouth Diseases Reference Laboratory, Key Laboratory of Animal Virology of Ministry of Agriculture, Lanzhou Veterinary Research Institute, Chinese Academy of Agricultural Sciences, Lanzhou, China.
authors.forename: Guoqing
authors.initials: G
authors.lastname: Wang
authors.affiliation: State Key Laboratory of Veterinary Etiological Biology, National Foot and Mouth Diseases Reference Laboratory, Key Laboratory of Animal Virology of Ministry of Agriculture, Lanzhou Veterinary Research Institute, Chinese Academy of Agricultural Sciences, Lanzhou, China.
authors.forename: Fan
authors.initials: F
authors.lastname: Yang
authors.affiliation: State Key Laboratory of Veterinary Etiological Biology, National Foot and Mouth Diseases Reference Laboratory, Key Laboratory of Animal Virology of Ministry of Agriculture, Lanzhou Veterinary Research Institute, Chinese Academy of Agricultural Sciences, Lanzhou, China.
authors.forename: Weijun
authors.initials: W
authors.lastname: Cao
authors.affiliation: State Key Laboratory of Veterinary Etiological Biology, National Foot and Mouth Diseases Reference Laboratory, Key Laboratory of Animal Virology of Ministry of Agriculture, Lanzhou Veterinary Research Institute, Chinese Academy of Agricultural Sciences, Lanzhou, China.
authors.forename: Ruoqing
authors.initials: R
authors.lastname: Mao
authors.affiliation: State Key Laboratory of Veterinary Etiological Biology, National Foot and Mouth Diseases Reference Laboratory, Key Laboratory of Animal Virology of Ministry of Agriculture, Lanzhou Veterinary Research Institute, Chinese Academy of Agricultural Sciences, Lanzhou, China.
authors.forename: Xiaoli
authors.initials: X
authors.lastname: Du
authors.affiliation: State Key Laboratory of Veterinary Etiological Biology, National Foot and Mouth Diseases Reference Laboratory, Key Laboratory of Animal Virology of Ministry of Agriculture, Lanzhou Veterinary Research Institute, Chinese Academy of Agricultural Sciences, Lanzhou, China.
authors.forename: Xiangle
authors.initials: X
authors.lastname: Zhang
authors.affiliation: State Key Laboratory of Veterinary Etiological Biology, National Foot and Mouth Diseases Reference Laboratory, Key Laboratory of Animal Virology of Ministry of Agriculture, Lanzhou Veterinary Research Institute, Chinese Academy of Agricultural Sciences, Lanzhou, China.
authors.forename: Chuntian
authors.initials: C
authors.lastname: Li
authors.affiliation: State Key Laboratory of Veterinary Etiological Biology, National Foot and Mouth Diseases Reference Laboratory, Key Laboratory of Animal Virology of Ministry of Agriculture, Lanzhou Veterinary Research Institute, Chinese Academy of Agricultural Sciences, Lanzhou, China.
authors.forename: Dan
authors.initials: D
authors.lastname: Li
authors.affiliation: State Key Laboratory of Veterinary Etiological Biology, National Foot and Mouth Diseases Reference Laboratory, Key Laboratory of Animal Virology of Ministry of Agriculture, Lanzhou Veterinary Research Institute, Chinese Academy of Agricultural Sciences, Lanzhou, China.
authors.forename: Keshan
authors.initials: K
authors.lastname: Zhang
authors.affiliation: Collaborative Innovation Center for Viral Immunology, Medical Research Institute, Wuhan University, Wuhan, China.
authors.forename: Hongbing
authors.initials: H
authors.lastname: Shu
authors.affiliation: State Key Laboratory of Veterinary Etiological Biology, National Foot and Mouth Diseases Reference Laboratory, Key Laboratory of Animal Virology of Ministry of Agriculture, Lanzhou Veterinary Research Institute, Chinese Academy of Agricultural Sciences, Lanzhou, China.
authors.forename: Xiangtao
authors.initials: X
authors.lastname: Liu
authors.affiliation: State Key Laboratory of Veterinary Etiological Biology, National Foot and Mouth Diseases Reference Laboratory, Key Laboratory of Animal Virology of Ministry of Agriculture, Lanzhou Veterinary Research Institute, Chinese Academy of Agricultural Sciences, Lanzhou, China haixuezheng@163.com.
authors.forename: Haixue
authors.initials: H
authors.lastname: Zheng
mesh_terms: D000086042:3C Viral Proteases; D000595:Amino Acid Sequence; D000818:Animals; D064113:CRISPR-Cas Systems; D002460:Cell Line; D003412:Cricetulus; D003546:Cysteine Endopeptidases / Q000235:genetics* / Q000276:immunology; D000071457:DEAD Box Protein 58 / Q000235:genetics* / Q000276:immunology; D004686:Encephalomyocarditis virus / Q000235:genetics / Q000276:immunology; D010450:Endopeptidases / Q000235:genetics* / Q000276:immunology; D004770:Enterovirus / Q000235:genetics / Q000276:immunology; D004771:Enteroviruses, Porcine / Q000235:genetics / Q000276:immunology; D004847:Epithelial Cells; D039603:Eukaryotic Initiation Factor-4G / Q000235:genetics* / Q000276:immunology; D029544:Foot-and-Mouth Disease Virus / Q000235:genetics* / Q000276:immunology; D005786:Gene Expression Regulation; D055785:Gene Knockdown Techniques; D057809:HEK293 Cells; D054884:Host-Pathogen Interactions; D006801:Humans; D011485:Protein Binding; D015398:Signal Transduction; D013045:Species Specificity; D013552:Swine; D014764:Viral Proteins / Q000235:genetics* / Q000276:immunology; D054334:Viral Regulatory and Accessory Proteins / Q000235:genetics* / Q000276:immunology
chemical_list: D039603:Eukaryotic Initiation Factor-4G; D014764:Viral Proteins; D054334:Viral Regulatory and Accessory Proteins; D010450:Endopeptidases; D003546:Cysteine Endopeptidases; D000086042:3C Viral Proteases; C088747:leader proteinase, foot-and-mouth disease virus; D000071457:DEAD Box Protein 58