Inadequate BiP availability defines endoplasmic reticulum stress.

Content Provider	Europe PMC
Author	Vitale, Milena Bakunts, Anush Orsi, Andrea Lari, Federica Tadè, Laura Danieli, Alberto Rato, Claudia Valetti, Caterina Sitia, Roberto Raimondi, Andrea Christianson, John C van Anken, Eelco
Editor	Walter, Peter Schekman, Randy
Copyright Year	2019
Abstract	How endoplasmic reticulum (ER) stress leads to cytotoxicity is ill-defined. Previously we showed that HeLa cells readjust homeostasis upon proteostatically driven ER stress, triggered by inducible bulk expression of secretory immunoglobulin M heavy chain (μs) thanks to the unfolded protein response (UPR; Bakunts et al., 2017). Here we show that conditions that prevent that an excess of the ER resident chaperone (and UPR target gene) BiP over µs is restored lead to µs-driven proteotoxicity, i.e. abrogation of HRD1-mediated ER-associated degradation (ERAD), or of the UPR, in particular the ATF6α branch. Such conditions are tolerated instead upon removal of the BiP-sequestering first constant domain (CH1) from µs. Thus, our data define proteostatic ER stress to be a specific consequence of inadequate BiP availability, which both the UPR and ERAD redeem.
Journal	eLife
Volume Number	8
PubMed Central reference number	PMC6417858
PubMed reference number	30869076
e-ISSN	2050084X
DOI	10.7554/elife.41168
Language	English
Publisher	eLife Sciences Publications, Ltd
Publisher Date	2019-03-14
Access Restriction	Open
Rights License	This article is distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use and redistribution provided that the original author and source are credited. © 2019, Vitale et al
Subject Keyword	unfolded protein response endoplasmic reticulum proteotoxicity ER stress chaperones BiP/GRP78 Human
Content Type	Text
Resource Type	Article
Subject	Immunology and Microbiology Neuroscience Medicine Biochemistry, Genetics and Molecular Biology