Potential for therapeutic manipulation of the UPR in disease

Abstract

Increased endoplasmic reticulum (ER) stress and the activated unfolded protein response (UPR) signaling associated with it play key roles in physiological processes as well as under pathological conditions. The UPR normally protects cells and re-establishes cellular homeostasis, but prolonged UPR activation can lead to the development of various pathologies. These features make the UPR signaling pathway an attractive target for the treatment of diseases whose pathogenesis is characterized by chronic activation of this pathway. Here, we focus on the molecular signaling pathways of the UPR and suggest possible ways to target this response for therapeutic purposes.

Fig. 1

Normal state. Proteins that enter the ER are folded and transported to the Golgi apparatus or other destination. GRP78 is bound to the luminal domains of PERK, IRE1, and ATF6

Fig. 2

ER stress state. During ER stress, GRP78 dissociates from PERK, IRE1, and ATF6. PERK and IRE1 oligomerize, forming a dimeric structure with a deep groove where peptide can bind. Upon oligomerization, PERK and IRE1 are auto-phosphorylated. PERK phosphorylates eIF2α, leading to attenuation in global protein synthesis. Phosphorylated eIF2α leads to translation and nuclear translocation of ATF4 and Nrf2. Activated IRE1 mediates unconventional mRNA splicing of XBP1 to generate XBP1s. IRE1 also recruits TRAF2 and ASK1 and leads to activation of JNK. ATF6 translocates to the Golgi apparatus and the cytoplasmic tail of ATF6 acts as a transcription factor to regulate UPR target genes

Fig. 3

ER stress in obesity and type 2 diabetes. a The regulatory subunits of PI3K, p85α and p85β, form a heterodimer, which dissociate from each other during insulin receptor signaling. Binding of p85α or β to XBP1s leads to nuclear translocation of XBP1s. In obesity conditions, interaction of p85α or β with XBP1s is disrupted, and it results in defective XBP1s nuclear translocation. b XBP1s interacts with FoxO1 and leads to proteasome-mediated degradation of FoxO1. Defective XBP1s nuclear translocation in obesity conditions results in accumulation of FoxO1 in the nucleus. c p38 MAPK phosphorylates XBP1s on Thr48 and Ser61 residues, and these phosphorylations are required for XBP1s nuclear translocation, which is defective in obesity conditions

Fig. 4

The action of chemical chaperones. a Current model. Chemical chaperones nonspecifically coat the surface of newly synthesized proteins and enhance their process of secretion. b Other possible model. Chemical chaperones enhance the transcription of genes that are involved in ER capacity, ER folding activity, and ERAD, by leading to activation of transcription factors or binding to transcription machinery. Chemical chaperones may act on calcium homeostasis by manipulating calcium influx into the ER lumen