Viral Hemorrhagic Septicemia Virus Activates Integrated Stress Response Pathway and Induces Stress Granules to Regulate Virus Replication

• Published in: Viruses Vol. 15; no. 2; p. 466
• Main Authors: Ramnani, Barkha, Powell, Shelby, Shetty, Adarsh G, Manivannan, Praveen, Hibbard, Brian R, Leaman, Douglas W, Malathi, Krishnamurthy
• Format: Journal Article
• Language: English
• Published: Switzerland MDPI AG 01-02-2023; MDPI
• Subjects: Animals; Antiviral Agents; Cellular control mechanisms; Development and progression; DNA Helicases; Double-stranded RNA; eIF-2 kinase; eIF2α phosphorylation; Endoplasmic reticulum; G3BP1; Genes; Genomes; GTPase-activating protein; Health aspects; Heat shock; Hemorrhage; Hemorrhagic septicemia; Infections; Interferon; Kinases; mRNA; Novirhabdovirus; Oxidative stress; Pathogenesis; PERK; Phosphorylation; Physiological aspects; Poly-ADP-Ribose Binding Proteins; Protein biosynthesis; Proteins; Replication; Rhabdoviruses; RNA Helicases; RNA polymerase; RNA Recognition Motif Proteins; Sepsis; Septicemia; Stress (Physiology); stress granule; Stress Granules; Transcription; Trout; VHSV; Viral infections; Virulence; Virus Replication; Virus research; Viruses; United States; United States > US; stress granule; G3BP1; translation; PERK; interferon; VHSV; eIF2α phosphorylation
• ISSN: 1999-4915; 1999-4915
• DOI: 10.3390/v15020466

Virus infection activates integrated stress response (ISR) and stress granule (SG) formation and viruses counteract by interfering with SG assembly, suggesting an important role in antiviral defense. The infection of fish cells by Viral Hemorrhagic Septicemia Virus (VHSV), activates the innate immune recognition pathway and the production of type I interferon (IFN). However, the mechanisms by which VHSV interacts with ISR pathway regulating SG formation is poorly understood. Here, we demonstrate that fish cells respond to heat shock, oxidative stress and VHSV infection by forming SG that localized key SG marker, Ras GTPase-activating protein (SH3 domain)-binding protein 1 (G3BP1). We show that PKR-like endoplasmic reticulum kinase (PERK), but not (dsRNA)-dependent protein kinase (PKR), is required for VHSV-induced SG formation. Furthermore, in VHSV Ia infected cells, PERK activity is required for IFN production, antiviral signaling and viral replication. SG formation required active virus replication as individual VHSV Ia proteins or inactive virus did not induce SG. Cells lacking G3BP1 produced increased IFN, antiviral genes and viral mRNA, however viral protein synthesis and viral titers were reduced. We show a critical role of the activation of ISR pathway and SG formation highlighting a novel role of G3BP1 in regulating VHSV protein translation and replication.