Enterovirus 71 induces dsRNA/PKR-dependent cytoplasmic redistribution of GRP78/BiP to promote viral replication

• Published in: Emerging microbes & infections Vol. 5; no. 1; pp. e23 - 12
• Main Authors: Jheng, Jia-Rong, Wang, Shin-Chyang, Jheng, Chao-Rih, Horng, Jim-Tong
• Format: Journal Article
• Language: English
• Published: United States Taylor & Francis Ltd 23.03.2016; Nature Publishing Group; Taylor & Francis Group
• Subjects: Cytoplasm - genetics; Cytoplasm - virology; eIF-2 Kinase - metabolism; Endoplasmic Reticulum - metabolism; endoplasmic reticulum stress; Endoplasmic Reticulum Stress - genetics; Endoplasmic Reticulum Stress - physiology; enterovirus 71; Enterovirus A, Human - genetics; Enterovirus A, Human - physiology; Eukaryotic Initiation Factor-2 - genetics; GRP78/BiP; Heat-Shock Proteins - genetics; Heat-Shock Proteins - metabolism; HEK293 Cells; Humans; Infections; Kinases; Original; Phosphorylation; Poly I-C - metabolism; protein kinase R; Proteins; Receptors, Peptide - genetics; Receptors, Peptide - metabolism; RNA, Double-Stranded - genetics; RNA, Double-Stranded - physiology; unfolded protein response; Up-Regulation; Viral Proteins - genetics; Virus Replication
• ISSN: 2222-1751; 2222-1751
• DOI: 10.1038/emi.2016.20

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.