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.
Highlights
It is well-established that accumulation of unfolded proteins in the endoplasmic reticulum (ER)—a condition referred to as ER stress—activates the unfolded protein response (UPR), which, in turn, mitigates the stress, most notably through enhancing the ER chaperone content to boost the protein folding capacity (Walter and Ron, 2011)
Based on insights obtained from ms-driven ER stress, we argue that these two UPR activation models are not mutually exclusive
To investigate in detail how the UPR sustains ER homeostatic readjustment to bulk ms expression, we exploited cells in which IRE1a was deleted and PERK and ATF6a were silenced with good efficiency (Bakunts et al, 2017), either individually or in combinations
Summary
It is well-established that accumulation of unfolded proteins in the endoplasmic reticulum (ER)—a condition referred to as ER stress—activates the unfolded protein response (UPR), which, in turn, mitigates the stress, most notably through enhancing the ER chaperone content to boost the protein folding capacity (Walter and Ron, 2011). What defines ER stress, and how ER stress may engender cytotoxicity, are poorly understood issues It is still debated what feature of ER stress activates the UPR. An important reason why these are still open questions is the wide-spread use of ER stress-eliciting drugs, such as tunicamycin (Tm), which inhibits N-glycosylation, or thapsigargin (Tg), which causes Ca2+ efflux from the ER (Walter and Ron, 2011). These drugs have pleiotropic effects and are inherently cytotoxic, obscuring important aspects of how ER homeostasis can be restored by virtue of the UPR or not. The cells successfully adapt to the proteostatic insult by expanding the ER both in size and in chaperone content, such that cell viability and growth are unaffected in the process, and UPR signaling subsides to a submaximal amplitude once homeostasis is restored (Bakunts et al, 2017)
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