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

After sensing misfolding proteins, GRP78 disengages from ATF6a or b isoforms. ATF6 translocates from ER to the Golgi apparatus where it is cleaved by resident proteases sphingosine-1-phosphate and sphingosine-2phosphate (S1P and S2P, respectively) to produce a cytosolic ATF6p50 fragment. The ATF6p50 fragment then translocates to the nucleus to modulate gene expression relating to increased ER folding capacity and ERAD pathway activation. 6, 7 The three branches of UPR signalling have reasonably distinct downstream functions, but they are engaged in a coordinated fashion and can act together. For example, XBP1 transcription can be induced by ATF6, and increased IRE1a expression is dependent on PERK-ATF4 pathway, 8 suggesting the complex interplay and crossregulation between the three branches of UPR pathway ( Figure 1 ).