title: Enterovirus 71 induces dsRNA/PKR-dependent cytoplasmic redistribution of GRP78/BiP to promote viral replication.
abstract: GRP78/BiP is an endoplasmic reticulum (ER) chaperone protein with the important function of maintaining ER homeostasis, and the overexpression of GRP78/BiP alleviates ER stress. Our previous studies showed that infection with enterovirus 71 (EV71), a (+)RNA picornavirus, induced GRP78/BiP upregulation; however, ectopic GRP78/BiP overexpression in ER downregulates virus replication and viral particle formation. The fact that a virus infection increases GRP78/BiP expression, which is unfavorable for virus replication, is counterintuitive. In this study, we found that the GRP78/BiP protein level was elevated in the cytoplasm instead of in the ER in EV71-infected cells. Cells transfected with polyinosinic-polycytidylic acid, a synthetic analog of replicative double-stranded RNA (dsRNA), but not with viral proteins, also exhibited upregulation and elevation of GRP78/BiP in the cytosol. Our results further demonstrate that EV71 infections induce the dsRNA/protein kinase R-dependent cytosolic accumulation of GRP78/BiP. The overexpression of a GRP78/BiP mutant lacking a KDEL retention signal failed to inhibit both dithiothreitol-induced eIF2α phosphorylation and viral replication in the context of viral protein synthesis and viral titers. These data revealed that EV71 infection might cause upregulation and aberrant redistribution of GRP78/BiP to the cytosol, thereby facilitating virus replication.
authors.affiliation: Graduate Institute of Biomedical Sciences and Department of Biochemistry and Molecular Biology, College of Medicine, Chang Gung University, Taoyuan 333, Taiwan.
authors.forename: Jia-Rong
authors.initials: JR
authors.lastname: Jheng
authors.affiliation: Graduate Institute of Biomedical Sciences and Department of Biochemistry and Molecular Biology, College of Medicine, Chang Gung University, Taoyuan 333, Taiwan.
authors.forename: Shin-Chyang
authors.initials: SC
authors.lastname: Wang
authors.affiliation: Graduate Institute of Biomedical Sciences and Department of Biochemistry and Molecular Biology, College of Medicine, Chang Gung University, Taoyuan 333, Taiwan.
authors.forename: Chao-Rih
authors.initials: CR
authors.lastname: Jheng
authors.affiliation: Graduate Institute of Biomedical Sciences and Department of Biochemistry and Molecular Biology, College of Medicine, Chang Gung University, Taoyuan 333, Taiwan.|Research Center for Emerging Viral Infections, College of Medicine, Chang Gung University, Taoyuan 333, Taiwan.|Department of Medical Research, Chang Gung Memorial Hospital, Taoyuan 333, Taiwan.|Research Center for Industry of Human Ecology and Graduate Institute of Health Industry Technology, Chang Gung University of Science and Technology, Taoyuan 333, Taiwan.
authors.forename: Jim-Tong
authors.initials: JT
authors.lastname: Horng
mesh_terms: D003593:Cytoplasm / Q000235:genetics* / Q000821:virology; D004721:Endoplasmic Reticulum / Q000378:metabolism; D000091342:Endoplasmic Reticulum Chaperone BiP; D059865:Endoplasmic Reticulum Stress / Q000235:genetics / Q000502:physiology; D029821:Enterovirus A, Human / Q000235:genetics* / Q000502:physiology*; D015852:Eukaryotic Initiation Factor-2 / Q000235:genetics; D057809:HEK293 Cells; D006360:Heat-Shock Proteins / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D010766:Phosphorylation; D011070:Poly I-C / Q000378:metabolism; D012330:RNA, Double-Stranded / Q000235:genetics / Q000502:physiology*; D018000:Receptors, Peptide / Q000235:genetics / Q000378:metabolism; D015854:Up-Regulation; D014764:Viral Proteins / Q000235:genetics; D014779:Virus Replication; D019892:eIF-2 Kinase / Q000378:metabolism
chemical_list: D000091342:Endoplasmic Reticulum Chaperone BiP; D015852:Eukaryotic Initiation Factor-2; C000717247:HSPA5 protein, human; D006360:Heat-Shock Proteins; C489304:KDELR1 protein, human; D012330:RNA, Double-Stranded; D018000:Receptors, Peptide; D014764:Viral Proteins; D019892:eIF-2 Kinase; D011070:Poly I-C