Abstract
Stress granules (SGs) are the sites of mRNA storage and related to the regulation of mRNA translation, which are dynamic structures in response to various environmental stresses and viral infections. Seneca Valley virus (SVV), an oncolytic RNA virus belonging to Picornaviridae family, can cause vesicular disease (VD) indistinguished from foot-and-mouth disease (FMD) and other pig VDs. In this study, we found that SVV induced SG formation in the early stage of infection in a PKR-eIF2α dependent manner, as demonstrated by the recruitment of marker proteins of G3BP1 and eIF4GI. Surprisingly, we found that downregulating SG marker proteins TIA1 or G3BP1, or expressing an eIF2α non-phosphorylatable mutant inhibited SG formation, but this inhibition of transient SG formation had no significant effect on SVV propagation. Depletion of G3BP1 significantly attenuated the activation of NF-κB signaling pathway. In addition, we found that SVV inhibited SG formation at the late stage of infection and 3C protease was essential for the inhibition depending on its enzyme activity. Furthermore, we also found that 3C protease blocked the SG formation by disrupting eIF4GI-G3BP1 interaction. Overall, our results demonstrate that SVV induces transient SG formation in an eIF2α phosphorylation and PKR-dependent manner, and that 3C protease inhibits SG formation by interfering eIF4GI-G3BP1 interaction.
Highlights
Seneca Valley virus (SVV) is a non-enveloped positive single-stranded RNA virus that belongs to the family Picornaviridae [1, 2]
There are four stress kinases involved in SG formation: double-stranded RNAdependent protein kinase (PKR) is activated by dsRNA during viral infection; protein kinase R-like endoplasmic reticulum kinase (PERK) senses unfolded proteins accumulation in the endoplasmic reticulum; heme-regulated inhibitor kinase (HRI) is activated when heme levels are changed by arsenite; and general control non-derepressible 2 kinase (GCN2) is activated under amino acid starvation [6]
The results indicated that eIF4GI could interact with GTPase-activating protein SH3-domain-binding protein 1 (G3BP1) in mock cells, whereas eIF4GI failed to interact with G3BP1 in the presence of SVV (Figure 7D)
Summary
Seneca Valley virus (SVV) is a non-enveloped positive single-stranded RNA virus that belongs to the family Picornaviridae [1, 2]. There are four stress kinases involved in SG formation: double-stranded RNA (dsRNA)dependent protein kinase (PKR) is activated by dsRNA during viral infection; protein kinase R-like endoplasmic reticulum kinase (PERK) senses unfolded proteins accumulation in the endoplasmic reticulum; heme-regulated inhibitor kinase (HRI) is activated when heme levels are changed by arsenite; and general control non-derepressible 2 kinase (GCN2) is activated under amino acid starvation [6] The activation of these kinases induces the phosphorylation of the alpha-subunit of eukaryotic initiation factor 2 (eIF2α), which shuts up most of initiation of eukaryotic translation and inhibits the formation of eIF2GTP-tRNAMi et ternary complex [7]. Our data indicate that SVV 3C blocks the SG formation by disrupting eIF4GI-G3BP1 interaction
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