Herpes Simplex Virus ? Suppresses The IRE1/XBP1 Signal Pathway Of The Unfolded Protein Response

The endoplasmic reticulum(ER)is an important cellular organelle that controls several critical aspects of cellular processes,such as biosynthesis,assembly,glycosylation,folding,and transport of proteins.Under conditions such as lipid metabolism,differentiation of secretory cells,DNA damage,and chemical insult,as well as viral infection,some misfolded or unfolded proteins accumulate in the lumen of the ER and cause ER stress.To reduce the protein load,cells activate the unfolded protein response(UPR)signal pathways to restore the homeostasis of the ER.However,under unresolved or intense ER stress,cells initiate the apoptotic pathway.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.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.Wild-type(WT),but not the UL41-null mutant HSV-1(R2621),decreased XBP1 mRNA induced by thapsigargin.Ne-vertheless,infection with both WT-HSV-1 and R2621 without drug pretreatment could reduce the mRNA and protein levels of XBPl(s),and additional mechanisms might contribute to this inhibition of XBP1(s)during the R2621 infection.The study will help us to better understand the mechanism how HSV-1 modulates the UPR and this will provide new strategies for treatment of HSV-1 infection.