title: Regulation of enterovirus 2A protease-associated viral IRES activities by the cell's ERK signaling cascade: Implicating ERK as an efficiently antiviral target.
abstract: In a previous study the ERK1/2 pathway was found to be crucially involved in positive regulation of the enterovirus A 71(EV-A71) IRES (vIRES), thereby contributing to the efficient replication of an important human enterovirus causing death in young children (<5yrs) worldwide. This study focuses on unraveling more about the detailed mechanism of ERK's involvement in this regulation of vIRES. Through the use of siRNAs and specifically pharmacological inhibitor U0126, the ERK cascade was shown to positively regulate EV-A71-mediated cleavage of eIF4GI that established the cellular conditions which favour vIRES-dependent translation. Site-directed mutagenesis of the viral 2A protease (2Apro) was undertaken to show that the positive regulation of virus replication by the ERK cascade was mediated through effects on both the cis-cleavage of the viral polyprotein by 2Aproand its trans-cleavage of cellular eIF4GI. This ERK-2Aprolinked network coordinating vIRES efficiency was also found in other important human enteroviruses. This identification of the ERK cascade as having a key role in maintaining the 2Aproproteolytic activity required to maximize enterovirus IRES activity, expands current understanding of the diverse functions of the ERK signaling cascade in the regulation of viral translation, therefore providing a potentially comprehensive drug target for anti-enterovirus infection.
authors.affiliation: Department of Microbiology, School of Basic Medical Sciences, Peking University Health Science Center, Beijing 100191, China.
authors.forename: Hao
authors.initials: H
authors.lastname: Duan
authors.affiliation: Department of Microbiology, School of Basic Medical Sciences, Peking University Health Science Center, Beijing 100191, China.
authors.forename: Meng
authors.initials: M
authors.lastname: Zhu
authors.affiliation: Department of Microbiology, School of Basic Medical Sciences, Peking University Health Science Center, Beijing 100191, China.
authors.forename: Qing
authors.initials: Q
authors.lastname: Xiong
authors.affiliation: Department of Microbiology, School of Basic Medical Sciences, Peking University Health Science Center, Beijing 100191, China.
authors.forename: Yuya
authors.initials: Y
authors.lastname: Wang
authors.affiliation: Department of Microbiology, School of Basic Medical Sciences, Peking University Health Science Center, Beijing 100191, China.
authors.forename: Chao
authors.initials: C
authors.lastname: Xu
authors.affiliation: State Key Laboratory of Natural and Biomimetic Drugs, Department of Medicinal Chemistry, School of Pharmaceutical Science, Peking University Health Science Center, Beijing 100191, China.
authors.forename: Jing
authors.initials: J
authors.lastname: Sun
authors.affiliation: State Key Laboratory of Natural and Biomimetic Drugs, Department of Medicinal Chemistry, School of Pharmaceutical Science, Peking University Health Science Center, Beijing 100191, China.
authors.forename: Chao
authors.initials: C
authors.lastname: Wang
authors.affiliation: Department of Microbiology, School of Basic Medical Sciences, Peking University Health Science Center, Beijing 100191, China.
authors.forename: Hao
authors.initials: H
authors.lastname: Zhang
authors.affiliation: State Key Laboratory of Natural and Biomimetic Drugs, Department of Medicinal Chemistry, School of Pharmaceutical Science, Peking University Health Science Center, Beijing 100191, China.
authors.forename: Ping
authors.initials: P
authors.lastname: Xu
authors.affiliation: Department of Microbiology, School of Basic Medical Sciences, Peking University Health Science Center, Beijing 100191, China. Electronic address: ypeng78@bjmu.edu.cn.
authors.forename: Yihong
authors.initials: Y
authors.lastname: Peng
mesh_terms: D000998:Antiviral Agents / Q000494:pharmacology*; D002070:Butadienes / Q000037:antagonists & inhibitors; D045744:Cell Line, Tumor; D029821:Enterovirus A, Human / Q000187:drug effects* / Q000201:enzymology; D004769:Enterovirus Infections / Q000188:drug therapy / Q000821:virology; D004789:Enzyme Activation / Q000187:drug effects*; D057809:HEK293 Cells; D006801:Humans; D000067556:Internal Ribosome Entry Sites / Q000235:genetics / Q000502:physiology*; D016297:Mutagenesis, Site-Directed; D009570:Nitriles / Q000037:antagonists & inhibitors; D020815:Polyproteins; D034741:RNA, Small Interfering; D012208:Rhabdomyosarcoma; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology*; D014764:Viral Proteins / Q000235:genetics / Q000378:metabolism*; D014779:Virus Replication / Q000187:drug effects
chemical_list: D000998:Antiviral Agents; D002070:Butadienes; D000067556:Internal Ribosome Entry Sites; D009570:Nitriles; D020815:Polyproteins; D034741:RNA, Small Interfering; C113580:U 0126; D014764:Viral Proteins
keywords: 2A protease; ERK; Enterovirus; IRES; eIF4G