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

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          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.

          Abstract

          Cells can adapt to chronic, mild ER stress without undergoing apoptosis. This is in part because the expression of pro-apoptotic pathway components is short-lived, which allows adaptive pathways to predominate.

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          Most cited references 48

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          Endoplasmic reticulum stress: cell life and death decisions.

           C. Xu (2005)
          Disturbances in the normal functions of the ER lead to an evolutionarily conserved cell stress response, the unfolded protein response, which is aimed initially at compensating for damage but can eventually trigger cell death if ER dysfunction is severe or prolonged. The mechanisms by which ER stress leads to cell death remain enigmatic, with multiple potential participants described but little clarity about which specific death effectors dominate in particular cellular contexts. Important roles for ER-initiated cell death pathways have been recognized for several diseases, including hypoxia, ischemia/reperfusion injury, neurodegeneration, heart disease, and diabetes.
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            CHOP is implicated in programmed cell death in response to impaired function of the endoplasmic reticulum.

            Cellular stress, particularly in response to toxic and metabolic insults that perturb function of the endoplasmic reticulum (ER stress), is a powerful inducer of the transcription factor CHOP. The role of CHOP in the response of cells to injury associated with ER stress was examined in a murine deficiency model obtained by homologous recombination at the chop gene. Compared with the wild type, mouse embryonic fibroblasts (MEFs) derived from chop -/- animals exhibited significantly less programmed cell death when challenged with agents that perturb ER function. A similar deficit in programmed cells death in response to ER stress was also observed in MEFs that lack CHOP's major dimerization partner, C/EBPbeta, implicating the CHOP-C/EBP pathway in programmed cell death. An animal model for studying the effects of chop on the response to ER stress was developed. It entailed exposing mice with defined chop genotypes to a single sublethal intraperitoneal injection of tunicamycin and resulted in a severe illness characterized by transient renal insufficiency. In chop +/+ and chop +/- mice this was associated with the early expression of CHOP in the proximal tubules followed by the development of a histological picture similar to the human condition known as acute tubular necrosis, a process that resolved by cellular regeneration. In the chop -/- animals, in spite of the severe impairment in renal function, evidence of cellular death in the kidney was reduced compared with the wild type. The proximal tubule epithelium of chop -/- animals exhibited fourfold lower levels of TUNEL-positive cells (a marker for programmed cell death), and significantly less evidence for subsequent regeneration. CHOP therefore has a role in the induction of cell death under conditions associated with malfunction of the ER and may also have a role in cellular regeneration under such circumstances.
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              ER stress induces cleavage of membrane-bound ATF6 by the same proteases that process SREBPs.

              ATF6 is a membrane-bound transcription factor that activates genes in the endoplasmic reticulum (ER) stress response. When unfolded proteins accumulate in the ER, ATF6 is cleaved to release its cytoplasmic domain, which enters the nucleus. Here, we show that ATF6 is processed by Site-1 protease (S1P) and Site-2 protease (S2P), the enzymes that process SREBPs in response to cholesterol deprivation. ATF6 processing was blocked completely in cells lacking S2P and partially in cells lacking S1P. ATF6 processing required the RxxL and asparagine/proline motifs, known requirements for S1P and S2P processing, respectively. Cells lacking S2P failed to induce GRP78, an ATF6 target, in response to ER stress. ATF6 processing did not require SCAP, which is essential for SREBP processing. We conclude that S1P and S2P are required for the ER stress response as well as for lipid synthesis.
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                Author and article information

                Contributors
                Role: Academic Editor
                Journal
                PLoS Biol
                pbio
                PLoS Biology
                Public Library of Science (San Francisco, USA )
                1544-9173
                1545-7885
                November 2006
                7 November 2006
                : 4
                : 11
                Affiliations
                [1 ] Howard Hughes Medical Institute, University of Michigan Medical Center, Ann Arbor, Michigan, United States of America
                [2 ] Department of Biological Chemistry, University of Michigan Medical Center, Ann Arbor, Michigan, United States of America
                [3 ] Department of Biophysics, Graduate School of Science, Kyoto University, Kyoto, Japan
                [4 ] Department of Pathology, University of Michigan Medical Center, Ann Arbor, Michigan, United States of America
                [5 ] Department of Chemical Engineering, University of Delaware, Newark, Delaware, United States of America
                [6 ] Department of Internal Medicine, University of Michigan Medical Center, Ann Arbor, Michigan, United States of America
                University of California San Francisco, United States of America
                Author notes
                * To whom correspondence should be addressed. E-mail: kaufmanr@ 123456umich.edu
                Article
                06-PLBI-RA-0091R3 plbi-04-11-28
                10.1371/journal.pbio.0040374
                1634883
                17090218
                Copyright: © 2006 Rutkowski et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
                Page count
                Pages: 18
                Categories
                Research Article
                Cell Biology
                In Vitro
                Eukaryotes
                Custom metadata
                Rutkowski DT, Arnold SM, Miller CN, Wu J, Li J, et al. (2006) Adaptation to ER stress is mediated by differential stabilities of pro-survival and pro-apoptotic mRNAs and proteins. PLoS Biol 4(11): e374. DOI: 10.1371/journal.pbio.0040374

                Life sciences

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