title: Requirement of the eukaryotic translation initiation factor 4F complex in hepatitis E virus replication.
abstract: Hepatitis E virus (HEV) infection, one of the foremost causes of acute hepatitis, is becoming a health problem of increasing magnitude. As other viruses, HEV exploits elements from host cell biochemistry, but we understand little as to which components of the human hepatocellular machinery are perverted for HEV multiplication. It is, however, known that the eukaryotic translation initiation factors 4F (eIF4F) complex, the key regulator of the mRNA-ribosome recruitment phase of translation initiation, serves as an important component for the translation and replication of many viruses. Here we aim to investigate the role of three subunits of the eIF4F complex: eukaryotic translation initiation factor 4A (eIF4A), eukaryotic translation initiation factor 4G (eIF4G) and eukaryotic translation initiation factor 4E (eIF4E) in HEV replication. We found that efficient replication of HEV requires eIF4A, eIF4G and eIF4E. Consistently, the negative regulatory factors of this complex: programmed cell death 4 (PDCD4) and eIF4E-binding protein 1 (4E-BP1) exert anti-HEV activities, which further illustrates the requirement for eIF4A and eIF4E in supporting HEV replication. Notably, phosphorylation of eIF4E induced by MNK1/2 activation is not involved in HEV replication. Although ribavirin and interferon-α (IFN-α), the most often-used off-label drugs for treating hepatitis E, interact with this complex, their antiviral activities are independent of eIF4E. In contrast, eIF4E silencing provokes enhanced anti-HEV activity of these compounds. Thus, HEV replication requires eIF4F complex and targeting essential elements of this complex provides important clues for the development of novel antiviral therapy against HEV.
authors.affiliation: Department of Gastroenterology and Hepatology, Erasmus MC-University Medical Center, Rotterdam, The Netherlands.
authors.forename: Xinying
authors.initials: X
authors.lastname: Zhou
authors.affiliation: Department of Gastroenterology and Hepatology, Erasmus MC-University Medical Center, Rotterdam, The Netherlands.
authors.forename: Lei
authors.initials: L
authors.lastname: Xu
authors.affiliation: Department of Gastroenterology and Hepatology, Erasmus MC-University Medical Center, Rotterdam, The Netherlands.
authors.forename: Yijin
authors.initials: Y
authors.lastname: Wang
authors.affiliation: Department of Gastroenterology and Hepatology, Erasmus MC-University Medical Center, Rotterdam, The Netherlands.
authors.forename: Wenshi
authors.initials: W
authors.lastname: Wang
authors.affiliation: Department of Gastroenterology and Hepatology, Erasmus MC-University Medical Center, Rotterdam, The Netherlands.
authors.forename: Dave
authors.initials: D
authors.lastname: Sprengers
authors.affiliation: Department of Gastroenterology and Hepatology, Erasmus MC-University Medical Center, Rotterdam, The Netherlands.
authors.forename: Herold J
authors.initials: HJ
authors.lastname: Metselaar
authors.affiliation: Department of Gastroenterology and Hepatology, Erasmus MC-University Medical Center, Rotterdam, The Netherlands.
authors.forename: Maikel P
authors.initials: MP
authors.lastname: Peppelenbosch
authors.affiliation: Department of Gastroenterology and Hepatology, Erasmus MC-University Medical Center, Rotterdam, The Netherlands. Electronic address: q.pan@erasmusmc.nl.
authors.forename: Qiuwei
authors.initials: Q
authors.lastname: Pan
mesh_terms: D000818:Animals; D051017:Apoptosis Regulatory Proteins / Q000378:metabolism; D045744:Cell Line, Tumor; D004261:DNA Replication; D039562:Eukaryotic Initiation Factor-4F / Q000378:metabolism*; D016751:Hepatitis E / Q000188:drug therapy / Q000821:virology; D016752:Hepatitis E virus / Q000187:drug effects / Q000502:physiology*; D006801:Humans; D016898:Interferon-alpha / Q000494:pharmacology; D051379:Mice; D018345:Mice, Knockout; D010766:Phosphorylation; D014176:Protein Biosynthesis; D016601:RNA-Binding Proteins / Q000378:metabolism; D012254:Ribavirin / Q000494:pharmacology; D014764:Viral Proteins / Q000378:metabolism; D014779:Virus Replication / Q000187:drug effects / Q000502:physiology*
chemical_list: D051017:Apoptosis Regulatory Proteins; D039562:Eukaryotic Initiation Factor-4F; D016898:Interferon-alpha; C114487:PDCD4 protein, human; C498443:Pdcd4 protein, mouse; D016601:RNA-Binding Proteins; D014764:Viral Proteins; D012254:Ribavirin
keywords: Eukaryotic translation initiation factor 4F complex; Hepatitis E virus; IFN-α; Ribavirin; eIF4E-binding protein 1