Endoplasmic Reticulum Stress: Its Role in Disease and Novel Prospects for Therapy

Figure 2

Overview of the three signaling branches of the ER stress response/UPR. In the absence of ER stress, ER luminal GRP78 associates with ER transmembrane proteins PERK, IRE1, and ATF6 to block their activation (shown as inactive UPR in the top right square). Upon ER stress, accumulating unfolded and misfolded proteins inside the ER sequester GRP78, thus dissociating this master regulator from all three transmembrane sensors and relieving their blockage. Activation of PERK entails homodimerization and autophosphorylation, leading to phosphorylation of eIF2𝛼, which terminates global protein translation, but exempts selected ER stress-associated proteins, such as ATF4. Activation of IRE1 also entails homodimerization and autophosphorylation. Endonuclease activity of activated IRE1 removes an intron from Xbp1 mRNA to generate a shorter splice variant that encodes transcription factor XBP1. ATF6 translocates to the Golgi, where it is proteolytically cleaved by S1 and S2 proteases to generate the transcriptionally active p50 fragment. All three transcription factors, ATF4, XBP1, and ATF6-p50 translocate into the nucleus where they regulate the expression of a variety of gene products collectively involved in managing ER stress. (See text for further details and references.)