NOXA contributes to the sensitivity of PERK‐deficient cells to ER stress

Gupta, Sanjeev; Giricz, Zoltán; Natoni, Alessandro; Donnelly, Neysan; Deegan, Shane; Szegezdi, Éva; Samali, Afshin

doi:10.1016/j.febslet.2012.10.002

Cited by 31 publications

(25 citation statements)

References 27 publications

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“…Consequently, knockout of Perk renders cells exquisitely sensitive to ER stress-induced death [ 10 ]. For this reason Perk +/+ and Perk −/− MEF cells were treated with a lower dose (25nM) of Tg as described previously [ 11 ]. Perk −/− MEF cells displayed lower SESTRIN 2 induction upon ER stress than their Perk +/+ counterparts (Figure 2B ).…”

Section: Resultsmentioning

confidence: 99%

Endoplasmic reticulum stress-mediated induction of SESTRIN 2 potentiates cell survival

et al. 2016

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Upregulation of SESTRIN 2 (SESN2) has been reported in response to diverse cellular stresses. In this study we demonstrate SESTRIN 2 induction following endoplasmic reticulum (ER) stress. ER stress-induced increases in SESTRIN 2 expression were dependent on both PERK and IRE1/XBP1 arms of the unfolded protein response (UPR). SESTRIN 2 induction, post ER stress, was responsible for mTORC1 inactivation and contributed to autophagy induction. Conversely, knockdown of SESTRIN 2 prolonged mTORC1 signaling, repressed autophagy and increased ER stress-induced cell death. Unexpectedly, the increase in ER stress-induced cell death was not linked to autophagy inhibition. Analysis of UPR pathways identified prolonged eIF2α, ATF4 and CHOP signaling in SESTRIN 2 knockdown cells following ER stress. SESTRIN 2 regulation enables UPR derived signals to indirectly control mTORC1 activity shutting down protein translation thus preventing further exacerbation of ER stress.

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Section: Resultsmentioning

confidence: 99%

Endoplasmic reticulum stress-mediated induction of SESTRIN 2 potentiates cell survival

et al. 2016

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“…It is known that inhibition of translation is critical in reducing the ER protein load following ER stress [ 62 ]; indeed, PERK -/- cells are more sensitive to ER stress than WT cells [ 5 , 62 ] presumably because PERK inhibition during ER stress sustains high levels of protein synthesis, thereby further exacerbating ER stress. ER stress in PERK -/- iMEFs has been proposed to promote oxidative stress and expression of the BH3-only protein NOXA to drive apoptosis [ 63 ]. In the context of our study this is an attractive hypothesis since NOXA is the only selective MCL1 antagonist within the BOP division of BCL2 proteins.…”

Section: Discussionmentioning

confidence: 99%

ERK1/2 signalling protects against apoptosis following endoplasmic reticulum stress but cannot provide long-term protection against BAX/BAK-independent cell death

2017

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Disruption of protein folding in the endoplasmic reticulum (ER) causes ER stress. Activation of the unfolded protein response (UPR) acts to restore protein homeostasis or, if ER stress is severe or persistent, drive apoptosis, which is thought to proceed through the cell intrinsic, mitochondrial pathway. Indeed, cells that lack the key executioner proteins BAX and BAK are protected from ER stress-induced apoptosis. Here we show that chronic ER stress causes the progressive inhibition of the extracellular signal-regulated kinase (ERK1/2) signalling pathway. This is causally related to ER stress since reactivation of ERK1/2 can protect cells from ER stress-induced apoptosis whilst ERK1/2 pathway inhibition sensitises cells to ER stress. Furthermore, cancer cell lines harbouring constitutively active BRAFV600E are addicted to ERK1/2 signalling for protection against ER stress-induced cell death. ERK1/2 signalling normally represses the pro-death proteins BIM, BMF and PUMA and it has been proposed that ER stress induces BIM-dependent cell death. We found no evidence that ER stress increased the expression of these proteins; furthermore, BIM was not required for ER stress-induced death. Rather, ER stress caused the PERK-dependent inhibition of cap-dependent mRNA translation and the progressive loss of pro-survival proteins including BCL2, BCLXL and MCL1. Despite these observations, neither ERK1/2 activation nor loss of BAX/BAK could confer long-term clonogenic survival to cells exposed to ER stress. Thus, ER stress induces cell death by at least two biochemically and genetically distinct pathways: a classical BAX/BAK-dependent apoptotic response that can be inhibited by ERK1/2 signalling and an alternative ERK1/2- and BAX/BAK-independent cell death pathway.

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“…In this study, Puma, Bid, death receptor 5 (DR5) and caspase-8 were shown to participate together with Noxa, suggesting either pathway redundancy or that caspase-8 is upstream of the mitochondrial pathway in this setting (see below). In addition, PERK-deficient MEFs, which are hypersensitive to ER stressors, also die in a Noxa-dependent manner when subjected to these stimuli [56].…”

Section: The Mitochondrial Pathwaymentioning

confidence: 99%

Cell death induced by endoplasmic reticulum stress

2015

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The endoplasmic reticulum (ER) is an organelle with multiple functions. The synthesis of transmembrane proteins and proteins that are to be secreted occur in this organelle. Many Author ManuscriptThis article is protected by copyright. All rights reserved conditions that impose stress to the cells, including hypoxia, starvation, infections and changes in secretory needs challenge the folding capacity of the cell and promote ER stress. The cellular response involves the activation of sensors that transduce signaling cascades with the aim to restore homeostasis. This is known as the Unfolded Protein Response (UPR), which also intersects with the Integrated Stress Response (ISR) that reduces protein synthesis through inactivation of the initiation factor eIF2α. Central to the UPR are the sensors PERK, IRE1 and ATF6, as well as other signaling nodes such as JNK and the downstream transcription factors XBP-1, ATF4 and CHOP. These proteins aim to restore homeostasis but they can also induce cell death, which has been shown to occur by necroptosis and, more commonly, through the regulation of Bcl-2 family proteins (Bim, Noxa and Puma) that leads to mitochondrial apoptosis. Additionally, ER stress and proteotoxic stress have been shown to induce TRAIL receptors and activation of Caspase-8.ER stress is a common feature in the pathology of numerous diseases as it plays a role in neurodegeneration, stroke, cancer, metabolic diseases and inflammation. Understanding how cells react to ER stress can accelerate discovery of drugs against these diseases. KeywordsEndoplasmic reticulum stress The endoplasmic reticulum and the Unfolded Protein Response sensorsThe endoplasmic reticulum (ER) is the organelle where transmembrane proteins and proteins that are going to be secreted are synthesized and folded. This organelle, however, is essential for multiple other cellular functions such as Ca 2+ buffering, biosynthesis of phospholipids and cholesterol. Synthesis of proteins, cholesterol and some metabolites is an ATP demanding process that also requires the right ionic strength. Disturbances in many homeostatic processes will thus lead to a state in which protein folding slows down (ER stress). The subsequent accumulation of misfolded or unfolded proteins will indicate problems in cellular homeostasis that frequently end up in cell death.Problems in protein folding can occur due to stressors apparently disparate such as starvation or viral infection. These stimuli promote the activation of a series of signals that promote synthesis of new proteins to cope with stress while reducing general protein synthesis [1,2]. This is called the Unfolded Protein Response (UPR). Another way by which the UPR aims to restore homeostasis is the stimulation of protein degradation via autophagy and the enhanced clearance of unfolded proteins by a process termed ER-Associated Degradation (ERAD).The UPR is orchestrated by three main sensors that reside in the membrane of the ER. These transmembrane proteins bind to the chaperone GRP78/BiP in the...

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NOXA contributes to the sensitivity of PERK‐deficient cells to ER stress

Cited by 31 publications

References 27 publications

Endoplasmic reticulum stress-mediated induction of SESTRIN 2 potentiates cell survival

Endoplasmic reticulum stress-mediated induction of SESTRIN 2 potentiates cell survival

ERK1/2 signalling protects against apoptosis following endoplasmic reticulum stress but cannot provide long-term protection against BAX/BAK-independent cell death

Cell death induced by endoplasmic reticulum stress

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