VMP1 affects endoplasmic reticulum stress sensitivity via differential modulation of the three unfolded protein response arms

• Published in: Cell reports (Cambridge) 2023-03, Vol.42 (3), p.112209-112209, Article 112209
• Main Authors: Li, Tao, Zhao, Hongyu, Guo, Gaofeng, Xia, Shuwei, Wang, Likun
• Format: Article
• Language: English
• Subjects: calcium; Calcium - metabolism; CP: Cell biology; eIF-2 Kinase - metabolism; Endoplasmic Reticulum Stress; Endoribonucleases - metabolism; ER stress; ER stress resistance; ER-mitochondria contact; integrated stress response; Membrane Proteins; mitochondrial stress; Protein Serine-Threonine Kinases - metabolism; Unfolded Protein Response; VMP1
• ISSN: 2211-1247; 2211-1247
• DOI: 10.1016/j.celrep.2023.112209

Consisting of three signaling pathways, the unfolded protein response (UPR) can be either protective or detrimental to cells that undergo ER stress. Elaborate regulation of the UPR is key to the cell-fate decision, but how it is achieved remains vague. Here, by studying cells deficient in vacuole membrane protein 1 (VMP1), a UPR regulator, we report a model of UPR regulation in which the three pathways are divergently controlled. Under basal conditions, calcium binding specifically activates PERK. Under ER stress, ER-mitochondria interaction-induced mitochondrial stress cooperates with PERK to suppress IRE1α and ATF6 by decelerating global protein synthesis. Such sophisticated regulation commits limited activation of the UPR yet refrains from UPR hyperactivation, protecting cells from chronic ER stress despite decreasing cell proliferation. Therefore, our study reveals interorganelle-interaction-dependent and calcium-dependent regulation of the UPR that dictates cell fate. [Display omitted] •Three UPR branches are differentially regulated in VMP1-deficient cells•Calcium directly activates PERK in VMP1-depleted cells independent of ER stress•Mitochondrial stress and PERK initiate ISR to blunt IRE1α and ATF6 in VMP1-KO cells•VMP1 deficiency confers chronic ER stress resistance despite basal growth defect Li et al. identify VMP1 as a regulator of the unfolded protein response (UPR). In VMP1-deleted cells, three branches of the UPR are differentially regulated through calcium disturbance and ER-mitochondria interplay. As a result, VMP1 deficiency protects cells from chronic ER stress despite impairing cell growth.