PT  - JOURNAL ARTICLE
AU  - Milena Vitale
AU  - Andrea Orsi
AU  - Anush Bakunts
AU  - Federica Lari
AU  - Laura Tadè
AU  - Angela Cattaneo
AU  - Roberto Sitia
AU  - Andrea Raimondi
AU  - Angela Bachi
AU  - Eelco van Anken
TI  - The unfolded protein response switches from pro-survival to pro-apoptotic to cap the extent of endoplasmic reticulum expansion
AID  - 10.1101/134726
DP  - 2017 Jan 01
TA  - bioRxiv
PG  - 134726
4099  - http://biorxiv.org/content/early/2017/05/05/134726.short
4100  - http://biorxiv.org/content/early/2017/05/05/134726.full
AB  - 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 ATF6α. Simultaneous abrogation of ER-associated degradation (ERAD) leads to chronic full-gear UPR activation and further ER expansion, but the UPR transducers IRE1α and PERK turn pro-apoptotic. Pro-survival XBP1 mRNA processing by IRE1α is then trumped since unspliced XBP1 mRNA is depleted and IRE1α’s endonuclease activity is unleashed against other RNAs. Thus, the IRE1α/XBP1 relay serves as a capacitor of ER expansion that heralds cell death if the expansion is deemed excessive.