The eIF2 kinase PERK and the integrated stress response facilitate activation of ATF6 during endoplasmic reticulum stress

Teske, Brian F.; Wek, Sheree A.; Bunpo, Piyawan; Cundiff, Judy K.; McClintick, Jeanette N.; Anthony, Tracy G.; Wek, Ronald C.

doi:10.1091/mbc.e11-06-0510

Cited by 323 publications

(301 citation statements)

References 78 publications

(135 reference statements)

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“…The UPR is a concerted and complex cellular response that is mediated through three ER transmembrane receptor proteins: double-stranded RNA-activated protein kinaselike endoplasmic reticulum kinase (PERK), inositol-requiring enzyme 1 (IRE1, also called ERN1) and activating transcription factor 6 (ATF6) [13,14] . In addition, glucose-regulated protein 78 kDa (GRP78, also called Bip) also plays an essential role in the UPR.…”

Section: Endoplasmic Reticulum Stress Suppresses Proteins Synthesis Amentioning

confidence: 99%

Endoplasmic reticulum stress: a novel mechanism and therapeutic target for cardiovascular diseases

2016

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Endoplasmic reticulum is a principal organelle responsible for folding, post-translational modifications and transport of secretory, luminal and membrane proteins, thus palys an important rale in maintaining cellular homeostasis. Endoplasmic reticulum stress (ERS) is a condition that is accelerated by accumulation of unfolded/misfolded proteins after endoplasmic reticulum environment disturbance, triggered by a variety of physiological and pathological factors, such as nutrient deprivation, altered glycosylation, calcium depletion, oxidative stress, DNA damage and energy disturbance, etc. ERS may initiate the unfolded protein response (UPR) to restore cellular homeostasis or lead to apoptosis. Numerous studies have clarified the link between ERS and cardiovascular diseases. This review focuses on ERS-associated molecular mechanisms that participate in physiological and pathophysiological processes of heart and blood vessels. In addition, a number of drugs that regulate ERS was introduced, which may be used to treat cardiovascular diseases. This review may open new avenues for studying the pathogenesis of cardiovascular diseases and discovering novel drugs targeting ERS.

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Section: Endoplasmic Reticulum Stress Suppresses Proteins Synthesis Amentioning

confidence: 99%

Endoplasmic reticulum stress: a novel mechanism and therapeutic target for cardiovascular diseases

2016

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“…Interfering with ER function activates the unfolded protein response (UPR), known as the ER stress response, which is a signal to recover ER function (Ma and Hendershot, 2004;Zhang and Kaufman, 2006;Rasheva and Domingos, 2009;White-Gilbertson et al, 2013). During ER stress, multiple signaling pathways are activated, including double-stranded RNA-activated protein kinase (PKR), the PKR-like ER kinase (PERK) and eukaryotic translation initiation factor 2 alpha (eIF2α), which suppress protein synthesis (Prostko et al, 1993;Teske et al, 2011). The UPR also activates synthesis of glucose-regulated protein 78 (GRP78), one of the endoplasmic reticulum chaperone molecules that can bind unfolded proteins and degrade misfolded proteins (Laitusis et al, 1999), and activation of transcription factors such as activating transcription factor (ATF6), inositol-requiring enzyme 1α (IRE1α), C/EBP homologous protein (CHOP), and caspase-12 (Urano et al, 2000;Yoshida et al, 2001;Lee et al, 2002;Back et al, 2006;Chung et al, 2011;.…”

Section: Introductionmentioning

confidence: 99%

Melatonin suppresses methamphetamine-triggered endoplasmic reticulum stress in C6 cells glioma cell lines

et al. 2017

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-Methamphetamine (METH) is a neurotoxic drug that causes brain damage by inducing neuronal and glial cell death together with glial cell hyperactivity-mediated progressive neurodegeneration. Previous studies have shown that METH induced glial cell hyperactivity and death via oxidative stress, the inflammatory response, and endoplasmic reticulum stress (ER stress) mechanisms, and melatonin could reverse these effects. However, the exact mechanism of the protective role of melatonin in METH-mediated ER stress has not been understood. This study investigated the protective effect of melatonin against METH toxicity-mediated ER stress in glial cells. Our study demonstrated that METH increased glial cell toxicity related to METH-induced ER stress by stimulating the unfolded protein response (UPR) to activate the expression of ER stress transducers, including phosphorylated doublestranded RNA-activated protein kinase (PKR)-like ER kinase (p-PERK), activating transcription factor (ATF6), and phosphorylated inositol-requiring enzyme 1 (p-IRE1). Moreover, the expression of binding immunoglobulin protein (Bip), CCAAT/enhancer-binding protein homologous protein (CHOP), caspase-12, phosphorylated eukaryotic translation initiation factor 2 alpha (p-eIF2α) and spliced X-box-binding protein-1 (XBP-1) mRNA were also increased. Melatonin reduced ER stress induced by METH toxicity by reducing the expression of ER stress response genes and proteins in a concentration-dependent manner. In addition, melatonin promoted the expression of Bip chaperone in a concentration-dependent manner. Taken together, our findings suggest that melatonin can protect against ER stress-induced glial cell death induced by METH.

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“…24,25 PERK is a single-pass mitochondria-associated ER membrane protein kinase that plays a principal role in restoring ER homeostasis. 26,27 Activated PERK phosphorylates its downstream target, eukaryotic initiation factor 2 alpha (eIF2a), leading to a global reduction in protein synthesis that provides the ER with an opportunity to correct protein folding. However, if UPR signals are unable to resolve ER stress (e.g., when the stressor persists or is intense), eIF2a increases expression of the proapoptotic protein, CIEBP homologous protein (CCAAT) element-binding protein homologous protein (CHOP), leading to cell death.…”

Section: Introductionmentioning

confidence: 99%

Inhibition of Eukaryotic Initiation Factor 2 Alpha Phosphatase Reduces Tissue Damage and Improves Learning and Memory after Experimental Traumatic Brain Injury

Dash

Hylin

Hood

et al. 2015

Journal of Neurotrauma

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Patients who survive traumatic brain injury (TBI) are often faced with persistent memory deficits. The hippocampus, a structure critical for learning and memory, is vulnerable to TBI and its dysfunction has been linked to memory impairments. Protein kinase RNA-like ER kinase regulates protein synthesis (by phosphorylation of eukaryotic initiation factor 2 alpha [eIF2a]) in response to endoplasmic reticulum (ER) stressors, such as increases in calcium levels, oxidative damage, and energy/glucose depletion, all of which have been implicated in TBI pathophysiology. Exposure of cells to guanabenz has been shown to increase eIF2a phosphorylation and reduce ER stress. Using a rodent model of TBI, we present experimental results that indicate that postinjury administration of 5.0 mg/kg of guanabenz reduced cortical contusion volume and decreased hippocampal cell damage. Moreover, guanabenz treatment attenuated TBI-associated motor, vestibulomotor, recognition memory, and spatial learning and memory dysfunction. Interestingly, when the initiation of treatment was delayed by 24 h, or the dose reduced to 0.5 mg/kg, some of these beneficial effects were still observed. Taken together, these findings further support the involvement of ER stress signaling in TBI pathophysiology and indicate that guanabenz may have translational utility.

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The eIF2 kinase PERK and the integrated stress response facilitate activation of ATF6 during endoplasmic reticulum stress

Cited by 323 publications

References 78 publications

Endoplasmic reticulum stress: a novel mechanism and therapeutic target for cardiovascular diseases

Endoplasmic reticulum stress: a novel mechanism and therapeutic target for cardiovascular diseases

Melatonin suppresses methamphetamine-triggered endoplasmic reticulum stress in C6 cells glioma cell lines

Inhibition of Eukaryotic Initiation Factor 2 Alpha Phosphatase Reduces Tissue Damage and Improves Learning and Memory after Experimental Traumatic Brain Injury

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