The unfolded protein response turns from pro-survival to pro-death to cap the extent of endoplasmic reticulum expansion

Insufficient folding capacity of the endoplasmic reticulum (ER) activates the unfolded protein response (UPR) to restore homeostasis. Yet, how the UPR achieves and evaluates ER homeostatic readjustment is poorly understood. In a HeLa cell model we show that, upon a severe proteostatic insult that eclipses the ER chaperone BiP, the UPR transitions from acute full-gear activation to chronic submaximal activation, when BiP is in excess again. As such, the UPR-driven ER expansion is pro-survival, primarily via the UPR transducer ATF6. Simultaneous abrogation of ER-associated degradation (ERAD) leads to chronic full-gear UPR activation and further ER expansion, but the UPR transducers IRE1 and PERK turn pro-apoptotic. Pro-survival XBP1 mRNA processing by IRE1 is then trumped since unspliced XBP1 mRNA is depleted and IRE1s endonuclease activity is unleashed against other RNAs. Thus, the IRE1/XBP1 relay serves as a capacitor of ER expansion that heralds cell death if the expansion is deemed excessive.