Immune regulation of the unfolded protein response at the mucosal barrier in viral infection

Wang, Ran; Moniruzzaman, Md.; Shuffle, Eric; Lourie, Rohan; Hasnain, Sumaira Z

The dissociation of GRP78 allows IRE1 dimerisation and activation of C-terminal endoribonuclease activity, which non-canonically splices a 26-base pair intron from the X-box binding protein 1 (XBP1) mRNA to produce the spliced form of XBP1 (sXBP1). This spliced form of XBP1 then translates into a transcription factor, which further translocates into the nucleus where it induces expression of a wide variety of genes including ER-associated chaperones and protein folding enzymes to increase ER size and folding capacity. A separate IRE1a-dependent decay of mRNA (RIDD) pathway is also described ( Figure 1 ). 1 RIDD degrades mRNAs to ultimately reduce ER load and subsequently reduce the UPR activation. However, with prolonged ER stress IRE1a becomes hyperactive and degrades mRNAs associated with anti-apoptotic responses, promoting cell death. IRE1b (also known as ERN2) is abundantly expressed by intestine and lung epithelial cells. 2 Compared to IRE1a, the role of IRE1b in the UPR is not very well studied. IRE1b may also be associated with RIDD, 3 which is closely related to intracellular parasite infections and anti-viral responses at mucosal surface. 4