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Viruses 2017, 9(9), 235; doi:10.3390/v9090235

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

1,†
,
1,†
,
1
,
1
,
1
and
1,2,3,*
1
Center for Public Health Research, Medical School, Nanjing University, Nanjing 210093, China
2
State Key Lab of Analytical Chemistry for Life Science, Nanjing University, Nanjing 210023, China
3
Jiangsu Laboratory for Molecular Medicines, Nanjing University, Nanjing 210093, China
These authors contributed equally.
*
Author to whom correspondence should be addressed.
Academic Editor: Curt Hagedorn
Received: 23 July 2017 / Revised: 12 August 2017 / Accepted: 16 August 2017 / Published: 23 August 2017
(This article belongs to the Section Antivirals & Vaccines)
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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. View Full-Text
Keywords: endoplasmic reticulum (ER); herpes simplex virus 1 (HSV-1); inositol-requiring enzyme 1 (IRE1); unfolded protein response (UPR); X-box binding protein 1 (XBP1) endoplasmic reticulum (ER); herpes simplex virus 1 (HSV-1); inositol-requiring enzyme 1 (IRE1); unfolded protein response (UPR); X-box binding protein 1 (XBP1)
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MDPI and ACS Style

Su, A.; Wang, H.; Li, Y.; Wang, X.; Chen, D.; Wu, Z. Opposite Roles of RNase and Kinase Activities of Inositol-Requiring Enzyme 1 (IRE1) on HSV-1 Replication. Viruses 2017, 9, 235.

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