Inadequate BiP Availability Defines Endoplasmic Reticulum Stress

Overview

Journal Elife

Specialty Biology

Date 2019 Mar 15

PMID 30869076

Citations 35

Authors

Milena Vitale

Anush Bakunts

Andrea Orsi

Federica Lari

Laura Tade

Alberto Danieli

Claudia Rato

Caterina Valetti

Roberto Sitia

Andrea Raimondi

John C Christianson

Eelco van Anken

Affiliations

Soon will be listed here.

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 (μ) 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 µ is restored lead to µ-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 (C1) from µ. Thus, our data define proteostatic ER stress to be a specific consequence of inadequate BiP availability, which both the UPR and ERAD redeem.

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