Figure 1.
ER stress and the unfolded protein response. A number of conditions such as disturbed lipid homeostasis, disturbed calcium signaling, oxidative stress, inhibition of glycosylation, increased protein synthesis, and decreased ER-associated degradation can cause ER stress and activate the unfolded protein response (UPR). The UPR is mediated by three ER membrane-associated proteins, PERK, IRE1α, and ATF6α, to induce translational and transcriptional changes upon ER stress. PERK phosphorylates eIF2α to attenuate general protein translation and decrease protein efflux into the ER. Phosphorylated eIF2α also selectively stimulates ATF4 translation to induce transcriptional regulation of UPR genes. IRE1α cleaves XBP1 mRNA to a spliced form of XBP1 that translates XBP1s to up-regulate UPR genes encoding factors involved in ER protein folding and degradation. ATF6α traffics to Golgi for cleavage by S1P and S2P to release pATF6α(N) that works synergistically or separately with XBP1s to regulate UPR gene expression.