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

By D. Rutkowski, Stacey M. Arnold, Corey N. Miller, Jun Wu, Jack C Li, K. Gunnison, K. Mori, A. S. Sadighi Akha, D. Raden, R. Kaufman. PLoS Biology, 2006

819 citations recorded by the source corpus.

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.

Subfields: Biotechnology, Cell Biology, Epidemiology

View Paper: https://www.semanticscholar.org/paper/73b168a319d2d7f861283759dd35ef7272718540

How researchers see this paper

The researchers whose trusted networks rank it highest, strongest advocate first. Every researcher gets a different order.

In Biotechnology

1. J. Malhotra
2. Kezhong Zhang
3. C. Hetz
4. Shiyu Wang
5. R. Kaufman
6. S. S. Cao

In Cell Biology

1. R. Kaufman
2. J. Malhotra
3. S. S. Cao
4. C. Hetz
5. Kezhong Zhang
6. Shiyu Wang
7. H. Chae
8. Hyung-Ryong Kim

In Epidemiology

1. R. Kaufman
2. J. Malhotra
3. S. S. Cao
4. C. Hetz
5. H. Chae
6. Hyung-Ryong Kim
7. Kezhong Zhang
8. Shiyu Wang

Citations in the corpus

• Tumorigenic and Immunosuppressive Effects of Endoplasmic Reticulum Stress in Cancer (2017, neutral): “MEFs exposed to persistent low-grade pharmacological ER stress resist subsequent ER insults, likely due to higher pro-survival BiP mRNA stability and reduced pro-apoptotic CHOP mRNA stability (Rutkowski et al., 2006).”
• Initiation and execution of lipotoxic ER stress in pancreatic β-cells (2008, background): “…possibility that ER Ca2+ depletion might enhance Ca2+ entry via store-operated (Smyth et al., 2006) or voltage-gated Ca2+ channels (Miura et al., 1997), thus raising cytosolic, and possibly mitochondrial, free Ca2+ levels (Rutter et al., 2006), to provide a cue for apoptosis (Choi et al., 2007).”
• ER stress: Autophagy induction, inhibition and selection (2015, background): “Mild to moderate ER stress-induced UPR signaling is seen as a compensatory mechanism, whereas severe and chronically prolonged ER stress deteriorates cellular functions and switches from an adaptation program to apoptosis to remove irreversibly injured cells.(18,19) Decreasing the ER protein load is”
• Intrinsically disordered proteins: regulation and disease. (2011, background): “[57] investigated what determines a mammalian cell to selectively adopt an apoptotic or adaptive response upon mild ER stress.”
• Antioxidants reduce endoplasmic reticulum stress and improve protein secretion (2008, background): “Induction of wtFVIII synthesis in these cells causes distention of the ER lumen, a characteristic of ER stress (15), and transcriptional activation of UPR genes (14).”
• The impact of the unfolded protein response on human disease (2012, background): “Most data support the notion that PERK–eIF2–ATF4 signaling is a primary determinant for apoptosis (Rutkowski et al., 2006).”
• The role for endoplasmic reticulum stress in diabetes mellitus. (2008, background): “This pattern of gene expression is probably due to the longer half-life of chaperones such as BiP, compared with proapoptotic genes such as CHOP (247), and may explain why -cells can endure 12 h of severe ER stress without reaching the point of no return for cell death.”
• Endoplasmic Reticulum Stress and Oxidative Stress in Cell Fate Decision and Human Disease (2014, background): “In vitro and animals studies demonstrated that CHOP is a master regulator of ER stress-induced apoptosis (143).”
• Glaucoma (2018, neutral): “Entorhinal cortex and hippocampus are affected early in AD [15].”