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Effect of the Viral Hemorrhagic Septicemia Virus Nonvirion Protein on Translation via PERK-eIF2α Pathway

Department of Biological Sciences, University of Toledo, 2801 West Bancroft Street, Toledo, OH 43606, USA
Department of Biological Sciences, Wright State University, 3640 Colonel Glenn Hwy, Dayton, OH 45435, USA
Institute of Marine and Environmental Technology, University of Maryland Baltimore County, Baltimore, MD 21202, USA
USDA/ARS, School of Freshwater Sciences, University of Wisconsin—Milwaukee, Milwaukee, Wisconsin, WI 53204, USA
Authors to whom correspondence should be addressed.
Viruses 2020, 12(5), 499;
Received: 8 April 2020 / Revised: 27 April 2020 / Accepted: 28 April 2020 / Published: 30 April 2020
(This article belongs to the Section Animal Viruses)
Viral hemorrhagic septicemia virus (VHSV) is one of the most deadly infectious fish pathogens, posing a serious threat to the aquaculture industry and freshwater ecosystems worldwide. Previous work showed that VHSV sub-genotype IVb suppresses host innate immune responses, but the exact mechanism by which VHSV IVb inhibits antiviral response remains incompletely characterized. As with other novirhabdoviruses, VHSV IVb contains a unique and highly variable nonvirion (NV) gene, which is implicated in viral replication, virus-induced apoptosis and regulating interferon (IFN) production. However, the molecular mechanisms underlying the role of IVb NV gene in regulating viral or cellular processes is poorly understood. Compared to the wild-type recombinant (rWT) VHSV, mutant VHSV lacking a functional IVb NV reduced IFN expression and compromised innate immune response of the host cells by inhibiting translation. VHSV IVb infection increased phosphorylated eukaryotic initiation factor 2α (p-eIF2α), resulting in host translation shutoff. However, VHSV IVb protein synthesis proceeds despite increasing phosphorylation of eIF2α. During VHSV IVb infection, eIF2α phosphorylation was mediated via PKR-like endoplasmic reticulum kinase (PERK) and was required for efficient viral protein synthesis, but shutoff of host translation and IFN signaling was independent of p-eIF2α. Similarly, IVb NV null VHSV infection induced less p-eIF2α, but exhibited decreased viral protein synthesis despite increased levels of viral mRNA. These findings show a role for IVb NV in VHSV pathogenesis by utilizing the PERK-eIF2α pathway for viral-mediated host shutoff and interferon signaling to regulate host cell response. View Full-Text
Keywords: VHSV; nonvirion; interferon; PERK; eIF2α phosphorylation; translation VHSV; nonvirion; interferon; PERK; eIF2α phosphorylation; translation
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Kesterson, S.P.; Ringiesn, J.; Vakharia, V.N.; Shepherd, B.S.; Leaman, D.W.; Malathi, K. Effect of the Viral Hemorrhagic Septicemia Virus Nonvirion Protein on Translation via PERK-eIF2α Pathway. Viruses 2020, 12, 499.

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