The impact of the unfolded protein response on human disease

Abstract

A central function of the endoplasmic reticulum (ER) is to coordinate protein biosynthetic and secretory activities in the cell. Alterations in ER homeostasis cause accumulation of misfolded/unfolded proteins in the ER. To maintain ER homeostasis, eukaryotic cells have evolved the unfolded protein response (UPR), an essential adaptive intracellular signaling pathway that responds to metabolic, oxidative stress, and inflammatory response pathways. The UPR has been implicated in a variety of diseases including metabolic disease, neurodegenerative disease, inflammatory disease, and cancer. Signaling components of the UPR are emerging as potential targets for intervention and treatment of human disease.

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.

Figure 2.

UPR signaling in diseases. Pathophysiological conditions such as hypoxia, elevated levels of fatty acids or cholesterol, oxidative stress, high or low glucose levels, and inflammatory cytokines induce ER stress and activate the UPR chronically. UPR signaling is interconnected with oxidative stress and inflammatory response pathways and involved in a variety of diseases including metabolic disease, inflammatory disease, and cancer. The three arms of the UPR, IRE1α-XBP1s, PERK-eIF2α phosphorylation-ATF4, and ATF6 are important for tumor cell survival and growth under hypoxic conditions. The UPR, IRE1α, and PERK can activate c-JUN N-terminal kinase (JNK) and NFκB to promote inflammation and apoptosis that contribute to inflammation in obesity and pancreatic β-cell death in diabetes. In addition, CHOP production in the PERK pathway exacerbates oxidative stress in diabetic states and atherosclerosis to aggravate the diseases.