PERK Activation at Low Glucose Concentration Is Mediated by SERCA Pump Inhibition and Confers Preemptive Cytoprotection to Pancreatic β-Cells

Moore, Claire E.; Omikorede, Omotola; Gomez, Edith; Willars, Gary B.; Herbert, Terence P.

doi:10.1210/jcem.96.2.zeg557a

Cited by 5 publications

(7 citation statements)

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“…14) and/or metabolic pathways. The UPR during hypoxia resembles the beta cell response to low non-stimulatory glucose concentrations where ATP and ER [Ca 2+ ] levels and protein synthesis are reduced [43,[48][49][50]. However, the inhibitory effect of hypoxia on the adaptive UPR is observed even in the presence of low glucose concentrations (not shown) suggesting additional mechanisms.…”

Section: Hypoxia Impairs Er-to-golgi Protein Trafficking In Beta Cellsmentioning

confidence: 92%

Hypoxia reduces ER-to-Golgi protein trafficking and increases cell death by inhibiting the adaptive unfolded protein response in mouse beta cells

et al. 2016

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Aims/hypothesis Hypoxia may contribute to beta cell failure in type 2 diabetes and islet transplantation. The adaptive unfolded protein response (UPR) is required for endoplasmic reticulum (ER) homeostasis. Here we investigated whether or not hypoxia regulates the UPR in beta cells and the role the adaptive UPR plays during hypoxic stress. Methods Mouse islets and MIN6 cells were exposed to various oxygen (O 2 ) tensions. DNA-damage inducible transcript 3 (DDIT3), hypoxia-inducible transcription factor (HIF)1α and HSPA5 were knocked down using small interfering (si)RNA; Hspa5 was also overexpressed. db/db mice were used. Results Hypoxia-response genes were upregulated in vivo in the islets of diabetic, but not prediabetic, db/db mice. In isolated mouse islets and MIN6 cells, O 2 deprivation (1-5% vs 20%; 4-24 h) markedly reduced the expression of adaptive UPR genes, including Hspa5, Hsp90b1, Fkbp11 and spliced Xbp1. Coatomer protein complex genes (Copa, Cope, Copg [also known as Copg1], Copz1 and Copz2) and ER-to-Golgi protein trafficking were also reduced, whereas apoptotic genes (Ddit3, Atf3 and Trb3 [also known as Trib3]), c-Jun N-terminal kinase (JNK) phosphorylation and cell death were increased. Inhibition of JNK, but not HIF1α, restored adaptive UPR gene expression and ER-to-Golgi protein trafficking while protecting against apoptotic genes and cell death following hypoxia. DDIT3 knockdown delayed the loss of the adaptive UPR and partially protected against hypoxia-induced cell death. The latter response was prevented by HSPA5 knockdown. Finally, Hspa5 overexpression significantly protected against hypoxia-induced cell death. Conclusions/interpretation Hypoxia inhibits the adaptive UPR in beta cells via JNK and DDIT3 activation, but independently of HIF1α. Downregulation of the adaptive UPR contributes to reduced ER-to-Golgi protein trafficking and increased beta cell death during hypoxic stress.

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Section: Hypoxia Impairs Er-to-golgi Protein Trafficking In Beta Cellsmentioning

confidence: 92%

Hypoxia reduces ER-to-Golgi protein trafficking and increases cell death by inhibiting the adaptive unfolded protein response in mouse beta cells

et al. 2016

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“…We next determined whether PERKi reduced PERK activity. Depletion of ER Ca 2ϩ stores causes activation of PERK and phosphorylation of its substrate eIF2␣ (31,32). Exposing INS1 832/13 cells 30 min to cyclopiazonic acid (CPA), an inhibitor of SERCA, led to PERK activation and phosphorylation of eIF2␣ (Fig.…”

Section: Inhibition Of Perk Activity Recapitulates ␤-Cell Dysfunctionsmentioning

confidence: 99%

Insulin Secretion and Ca2+ Dynamics in β-Cells Are Regulated by PERK (EIF2AK3) in Concert with Calcineurin

Wang

McGrath

Kopp

et al. 2013

Journal of Biological Chemistry

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Background: A genetic deficiency in protein kinase R (PKR)-like endoplasmic reticulum kinase (PERK) in human and mice results in insulin-dependent diabetes. Results: Acute inhibition of PERK impairs insulin secretion, secretagogue-stimulated Ca 2ϩ influx, and sarcoplasmic endoplasmic reticulum Ca 2ϩ -ATPase activity through a calcineurin-dependent pathway. Conclusion: PERK and calcineurin regulates Ca 2ϩ dynamics underlying insulin secretion. Significance: Our findings provide insights into the intracellular mechanisms underlying stimulated insulin secretion.

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“…Lower SERCA activity, e.g. following disturbed lipid metabolism, glucose starvation or inflammatory mediators, is a well-known phenomenon during ER-stress-dependent toxicity (Cardozo et al, 2005;Fu et al, 2011;Hara et al, 2014;Moore et al, 2011). Likewise, altered IP 3 R activity and increases in passive Ca 2+ leak from the ER are hallmarks of ER-stressed cells (Kiviluoto et al, 2013) (see also below).…”

Section: Camentioning

confidence: 99%

“…rendering the ER lumen more reducing) (Avezov et al, 2013;Birk et al, 2013;Enyedi et al, 2010). Although the mechanistic basis for this drop remains to be explored, it is probable that lowering ER Ca 2+ levels during chronic ER stress (Cardozo et al, 2005;Fu et al, 2011;Hara et al, 2014;Moore et al, 2011) mediates a hypo-oxidizing ER environment. With regards to the reductive activation of ATF6 (see below), ER hypo-oxidation, in turn, will stimulate stress signals.…”

Section: Box 2 Reactive Oxygen Speciesmentioning

confidence: 99%

Redox controls UPR to control redox

Eletto

Chevet

Argon

et al. 2014

Journal of Cell Science

154

137

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In many physiological contexts, intracellular reduction-oxidation (redox) conditions and the unfolded protein response (UPR) are important for the control of cell life and death decisions. UPR is triggered by the disruption of endoplasmic reticulum (ER) homeostasis, also known as ER stress. Depending on the duration and severity of the disruption, this leads to cell adaptation or demise. In this Commentary, we review reductive and oxidative activation mechanisms of the UPR, which include direct interactions of dedicated protein disulfide isomerases with ER stress sensors, protein S-nitrosylation and ER Ca 2+ efflux that is promoted by reactive oxygen species. Furthermore, we discuss how cellular oxidant and antioxidant capacities are extensively remodeled downstream of UPR signals. Aside from activation of NADPH oxidases, mitogen-activated protein kinases and transcriptional antioxidant responses, such remodeling prominently relies on ER-mitochondrial crosstalk. Specific redox cues therefore operate both as triggers and effectors of ER stress, thus enabling amplification loops. We propose that redox-based amplification loops critically contribute to the switch from adaptive to fatal UPR.

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PERK Activation at Low Glucose Concentration Is Mediated by SERCA Pump Inhibition and Confers Preemptive Cytoprotection to Pancreatic β-Cells

Cited by 5 publications

References 0 publications

Hypoxia reduces ER-to-Golgi protein trafficking and increases cell death by inhibiting the adaptive unfolded protein response in mouse beta cells

Hypoxia reduces ER-to-Golgi protein trafficking and increases cell death by inhibiting the adaptive unfolded protein response in mouse beta cells

Insulin Secretion and Ca2+ Dynamics in β-Cells Are Regulated by PERK (EIF2AK3) in Concert with Calcineurin

Redox controls UPR to control redox

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