Opposite Roles of RNase and Kinase Activities of Inositol-Requiring Enzyme 1 (IRE1) on HSV-1 Replication

Abstract

In response to the endoplasmic reticulum (ER) stress induced by herpes simplex virus type 1 (HSV-1) infection, host cells activate the unfolded protein response (UPR) to reduce the protein-folding burden in the ER. The regulation of UPR upon HSV-1 infection is complex, and the downstream effectors can be detrimental to viral replication. Therefore, HSV-1 copes with the UPR to create a beneficial environment for its replication. UPR has three branches, including protein kinase RNA (PKR)-like ER kinase (PERK), inositol-requiring enzyme 1 (IRE1), and activated transcription factor 6 (ATF6). IRE1α is the most conserved branch of UPR which has both RNase and kinase activities. Previous studies have shown that IRE1α RNase activity was inactivated during HSV-1 infection. However, the effect of the two activities of IRE1α on HSV-1 replication remains unknown. Results in this study showed that IRE1α expression was up-regulated during HSV-1 infection. We found that in HEC-1-A cells, increasing RNase activity, or inhibiting kinase activity of IRE1α led to viral suppression, indicating that the kinase activity of IRE1α was beneficial, while the RNase activity was detrimental to viral replication. Further evidence showed that the kinase activity of IRE1α leads to the activation of the JNK (c-Jun N-terminal kinases) pathway, which enhances viral replication. Taken together, our evidence suggests that IRE1α is involved in HSV-1 replication, and its RNase and kinase activities play differential roles during viral infection.

KSHV activates unfolded protein response sensors but suppresses downstream transcriptional responses to support lytic replication

“…Moreover, HSV-1 glycoprotein B (gB) binds and inhibits PERK to support robust viral protein synthesis [57]. Interestingly, ectopic expression of FLAG-tagged XBP1s inhibits HSV-1 replication [101], consistent with our findings in KSHV infection models. By contrast, human cytomegalovirus (HCMV) lytic replication in fibroblast cells selectively activates PERK and IRE1, but not ATF6 [55].…”

“…Many viruses modulate the UPR, including other herpesviruses. Herpes simplex virus type 1 (HSV-1) has been shown to dysregulate IRE1 activity [99]; HSV-1 infected cells displayed increased IRE1 protein levels but diminished IRE1 RNase activity, and treatment with the IRE1 inhibitor STF-083010 [100] diminished viral replication [101]. Moreover, HSV-1 glycoprotein B (gB) binds and inhibits PERK to support robust viral protein synthesis [57].…”

“…Beyond the aforementioned XBP1s transcription program, IRE1 can activate the JNK signalling pathway [107], which plays important roles in viral replication, cellular stress responses, and cell fate [108,109]. For HSV-1, IRE1 activation could activate JNK, which has been shown to support viral replication in multiple cell types [101]. JNK has also been shown to play important roles in KSHV infection; de novo infection triggers JNK activation, and ER stress-induced JNK activation can reactivate KSHV from latency [110,111].…”

Herpesviruses and the Unfolded Protein Response

“…HSV-1 replication has been shown to induce ATF6 cleavage but there is no impact on the ATF6 target gene BiP suggesting that HSV-1 blocks signaling of the ATF6 branch of the UPR [186]. IRE1 has also been reported to be activated during HSV-1 infection but its RNase activity is suppressed through an unknown mechanism [196]. Alternatively, IRE1 kinase activity and the IRE1-dependent phosphorylation of JNK was reported to promote virus replication, whereas XBP1s overexpression inhibits virus production.…”

“…Alternatively, IRE1 kinase activity and the IRE1-dependent phosphorylation of JNK was reported to promote virus replication, whereas XBP1s overexpression inhibits virus production. This suggests that HSV-1 fine-tunes IRE1 signaling to suppress XBP1s activation while activating the JNK pathway to promote HSV-1 replication [196]. Since XBP1s inhibits HSV-1, restoring IRE1 RNase activity may be one potential avenue of investigation for inhibiting HSV-1.…”