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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.

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BiP/GRP78, ER stress, cell biology, chaperones, endoplasmic reticulum, human, proteotoxicity, unfolded protein response, Endoplasmic Reticulum Chaperone BiP, Endoplasmic Reticulum Stress, Endoplasmic Reticulum-Associated Degradation, Epithelial Cells, HeLa Cells, Heat-Shock Proteins, Humans, Proteostasis, Unfolded Protein Response