The unfolded protein response induced by Tembusu virus infection

Abstract

BackgroundTembusu virus (TMUV), classified in the genus Flavivirus, causes reduced egg production and neurological problems in poultry. Flavivirus replication depends on the host endoplasmic reticulum (ER) and induces ER stress that leads to activation of the cellular unfolded protein response (UPR), an important signalling pathway that regulates many biological functions involved in viral pathogenesis and innate immunity. However, the mechanism of TMUV-induced UPR activation remains unclear.ResultsIn this study, we systematically investigated the three UPR pathways in TMUV-infected BHK-21 cells. Our results showed that expression of glucose-related protein 78 (GRP78) and GRP94 was upregulated during the course of TMUV infection. We then demonstrated that TMUV activated the PERK pathway in the early stage of infection, resulting in upregulation of ATF4, GADD34 and CHOP, with CHOP induction leading to caspase-3 activation. We also found the IRE1 pathway to be activated, leading to splicing of X box binding protein 1 (XBP1) mRNA and enhanced expression of p58IPK. Finally, we observed increased expression of ATF6 and activity of ER stress-response elements, suggesting stimulation of the ATF6 pathway. In addition, ATF6 pathway activation correlated with the induction of downstream chaperones calnexin, calreticulin, ERp57 and PDI. UPR activity was also observed by the marked elevation in GRP78 and sXBP1 levels in TMUV-infected DF-1 cells.ConclusionsThis is the first report that TMUV infection-induced ER stress activates three branches of the UPR, and these results lay the foundation for elucidating the pathogenesis of TMUV and understanding the inherent mechanism of TMUV infection as well as the host response.

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“…When cells are stimulated, PERK is first isolated from GRP78 and activated to phosphorylate eIF2α at serine residue, thus preventing protein synthesis by inhibiting mRNA translation. 44 Mechanism study showed that SiNPs block the binding of GRP78 and PERK, activate eIF2α phosphorylation, and promote the downstream signal transduction to weaken or terminate when the ER emergency continues or is serious. 45 Phosphorylated eIF2α is no longer able to associate with the translation initiation complex, leading to decreased global protein synthesis, which in turn, stimulates the expression of C/EBPhomologous protein (CHOP), causing apoptosis.…”