Introduction Endoplasmic reticulum (ER) plays important roles in viral replication. Massive viral proteins entering the ER can trigger ER stress. The ER stress is marked by the activation of a series of signalling pathways, called the unfolded protein response (UPR), which consists of three distinct, yet related, signal pathways, PERK, IRE1 and ATF6. The PRKR-like ER kinase (PERK) signalling branch has been the focus of investigation on its roles during HSV gene expression. In contrast, there have been little studies on roles of the IRE1 branch of the UPR on HSV replication.
Methods Western blot, RT-PCR, RNA interference and in cell western method were used in the study.
Results We showed that HSV-1 replication was inhibited by the phosphorylation of the IRE1 (p-IRE1) pathway. We also detected the mRNA expression of spliced X box-binding protein 1 (XBP1s), which was activated by p-IRE1. IRE1 mRNA was upregulated by viral infection, but XBP1s was not affected, which indicated that viral replication is not associated with spliced XBP1 signal pathway. It is known that cJUN NH2-terminal kinases JNK [JNKs; also known as stress-activated protein kinases (SAPKs)] is another downstream component of IRE1 and JNK is known to be activated by infected cell polypeptide 0 (ICP0), the immediate early protein of HSV-1. Our results revealed that the JNK activation was attenuated following the IRE1 inactivation. Inhibition of ire1 function by RNA interference (siRNA) could block the viral replication and JNK activation, suggesting that IRE1 pathway is required for facilitating viral gene expression and the inhibition of IRE1 activation blocks viral replication.
Conclusion The identification of roles of the IRE1 branch of ER stress in HSV-1 replication will provide new insight to the HSV-1 pathogenesis and may lead to new therapeutic targets.
Disclosure of interest statement No conflict of interest in the development of this study.
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