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Endoplasmic reticulum (ER) stress and the consecutive activation of the Unfolded Protein Response (UPR) contribute to the pathogenesis of several diseases including diabetes, neurodegenerative diseases and inflammation. However, the UPR also plays a crucial adaptive role in the acquisition and maintenance of the phenotype of cells that secrete large amounts of proteins. After a brief overview of this physiological role of the UPR in immunoglobulin-secreting plasmocytes and pancreatic acinar cells, this chapter will mainly focus on insulin-secreting pancreatic β-cells that play a critical role in glucose homeostasis. Upon their stimulation with glucose and other nutrients, these cells display a rise in mitochondrial metabolism, ATP production and Ca2+ pumping in the ER, in parallel to the stimulation of protein (preferentially proinsulin) biosynthesis. These metabolic and functional features give rise to a peculiar pattern of acute regulation of the UPR by nutrients. At low non-stimulatory glucose concentrations, when intracellular ATP, [Ca2+]ER and protein synthesis are low, the IRE1-XBP1 branch of the UPR is at its lowest level of activation while the PERK-eIF2α-ATF4 branch of the UPR is maximally activated, with strong upregulation of Integrated Stress Response (ISR) genes. Upon glucose stimulation, the rise in ATP and [Ca2+]ER leads to PERK-eIF2α dephosphorylation, inhibition of the ISR and derepression of protein synthesis. Consequent activation of the IRE1-XBP1 branch of the UPR upregulates the expression of chaperones, foldases, ER to Golgi transport and ER-associated degradation machinery that help the β-cell coping with the large increase in proinsulin biosynthesis. This opposite glucose regulation of the PERK and IRE1 arms of the UPR is rapid and dynamic, suggesting its importance in the physiological adaptation of the β-cell to changes in nutrient supply.
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Bensellam, M., Gilon, P., & Jonas, J.-C. (2012). Physiological ER Stress: The Model of Insulin-Secreting Pancreatic β-Cells. In Patrizia Agostinis;Afshin Samali (ed.), Endoplasmic Reticulum Stress in Health and Disease (p. p. 185-211). Springer. https://doi.org/10.1007/978-94-007-4351-9