Adaptation to ER Stress Is Mediated by Differential Stabilities of Pro-Survival and Pro-Apoptotic mRNAs and Proteins

TLDR

Unfolded proteins in the ER trigger the unfolded protein response (UPR), which activates both apoptotic and adaptive pathways, yet the mechanism by which the response selectively promotes adaptation remains unclear. The study aims to reconstitute an adaptive ER stress response in a cell culture system. By monitoring UPR gene expression pathways that drive adaptation or apoptosis, the authors show that mild ER stress activates all UPR sensors in cultured cells. Survival during mild stress is achieved because pro‑apoptotic mRNAs and proteins are intrinsically unstable, whereas adaptive chaperone expression persists, demonstrating that post‑transcriptional and post‑translational regulation enables cells to avert death.

Abstract

The accumulation of unfolded proteins in the endoplasmic reticulum (ER) activates a signaling cascade known as the unfolded protein response (UPR). Although activation of the UPR is well described, there is little sense of how the response, which initiates both apoptotic and adaptive pathways, can selectively allow for adaptation. Here we describe the reconstitution of an adaptive ER stress response in a cell culture system. Monitoring the activation and maintenance of representative UPR gene expression pathways that facilitate either adaptation or apoptosis, we demonstrate that mild ER stress activates all UPR sensors. However, survival is favored during mild stress as a consequence of the intrinsic instabilities of mRNAs and proteins that promote apoptosis compared to those that facilitate protein folding and adaptation. As a consequence, the expression of apoptotic proteins is short-lived as cells adapt to stress. We provide evidence that the selective persistence of ER chaperone expression is also applicable to at least one instance of genetic ER stress. This work provides new insight into how a stress response pathway can be structured to allow cells to avert death as they adapt. It underscores the contribution of posttranscriptional and posttranslational mechanisms in influencing this outcome.