On December 7th, 2016, researchers at Dr. Chunfu Zheng’s group published an article entitled “Herpes Simplex Virus 1 UL41 Protein Suppresses the IRE1/XBP1 Signal Pathway of the Unfolded Protein Response via its RNase activity” in Journal of Virology. Our results show for the first time that HSV-1 tegument protein UL41 suppressed the IRE1/XBP1 signal pathway via reducing the accumulation of XBP1 mRNA and characterization of the underlying molecular mechanism provides new insight into the modulation of unfolded protein response (UPR) by HSV-1.
During HSV-1 replication, the rapid production of large quantities of viral proteins may induce the UPR and HSV-1 selectively modulates the UPR to benefit its replication. The IRE1/XBP1 pathway is the most conserved UPR branch in eukaryotic cells. Upon activation, IRE1 dimerizes and transphosphorylates itself, and activated IRE1 removes a 26-nucleotide intron from X box-binding protein 1 (XBP1) mRNA to form a spliced XBP1 (XBP1(s)), which is subsequently translated into a potent transcription factor. Then XBP1(s) translocates to the nucleus and induces expression of genes that enhance the ER protein-folding capacity, phospholipid biosynthesis and ER-associated protein degradation (ERAD). Here we uncovered a role of HSV-1 protein UL41 in inhibiting the IRE1/XBP1 signal pathway. Ectopic expression of UL41 decreased the expression of XBP1 and blocked XBP1 splicing activation induced by the ER stress inducer of thapsigargin. Wild-type (WT), but not the UL41-null mutant HSV-1 (R2621), decreased XBP1 mRNA induced by thapsigargin. Nevertheless, infection with both WT-HSV-1 and R2621 without drug pretreatment could reduce the mRNA and protein levels of XBP1(s), and additional mechanisms might contribute to this inhibition of XBP1(s) during the R2621 infection. Taking these findings together, our results reveal XBP1 as a novel target of UL41 and provide insights into the mechanism by which HSV-1 modulates the IRE1/XBP1 pathway.
Mr. Pengchao Zhang and Ms. Chenhe Su are the co-first authors and Mr. Zhangtao Jiang is the co-author. Prof. Chunfu Zheng is the corresponding author. Work in the Zheng laboratory relevant to this article was supported by grants from the National Natural Science Foundation of China (81371795 and 81571974).