Acute hypoxia induces apoptosis of pancreatic β-cell by activation of the unfolded protein response and upregulation of CHOP

Type 1 diabetes (T1D) is an autoimmune disease characterized by islet inflammation and progressive pancreatic β cell destruction. The disease is triggered by a combination of genetic and environmental factors, but the mechanisms leading to the triggering of early innate and late adaptive immunity and consequent progressive pancreatic β cell death remain unclear. The insulin-producing β cells are active secretory cells and are thus particularly sensitive to endoplasmic reticulum (ER) stress. ER stress plays an important role in the pathologic pathway leading to autoimmunity, islet inflammation, and β cell death. We show here that group B coxsackievirus (CVB) infection, a putative causative factor for T1D, induces a partial ER stress in rat and human β cells. The activation of the PERK/ATF4/CHOP branch is blunted while the IRE1α branch leads to increased spliced XBP1 expression and c-Jun N-terminal kinase (JNK) activation. Interestingly, JNK1 activation is essential for CVB amplification in both human and rat β cells. Furthermore, a chemically induced ER stress preceding viral infection increases viral replication, in a process dependent on IRE1α activation. Our findings show that CVB tailors the unfolded protein response in β cells to support their replication, preferentially triggering the pro-viral IRE1α/XBP1s/JNK1 pathway while blocking the pro-apoptotic PERK/ATF4/CHOP pathway.

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IRE1 inhibition perturbs the unfolded protein response in a pancreatic β-cell line expressing mutant proinsulin, but does not sensitize the cells to apoptosis

BMC Cell Biology ◽

10.1186/1471-2121-15-29 ◽

2014 ◽

Vol 15 (1) ◽

pp. 29 ◽

Cited By ~ 13

Author(s):

Liling Zhang ◽

Courtney Nosak ◽

Pietro Sollazzo ◽

Tanya Odisho ◽

Allen Volchuk

Keyword(s):

Unfolded Protein Response ◽

Cell Line ◽

Pancreatic Β Cell ◽

Β Cell ◽

Unfolded Protein ◽

The Unfolded Protein Response ◽

Protein Response

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Endoplasmic reticulum stress and the unfolded protein response in pancreatic islet inflammation

Journal of Molecular Endocrinology ◽

10.1530/jme-15-0306 ◽

2016 ◽

Vol 57 (1) ◽

pp. R1-R17 ◽

Cited By ~ 31

Author(s):

Kira Meyerovich ◽

Fernanda Ortis ◽

Florent Allagnat ◽

Alessandra K Cardozo

Keyword(s):

Endoplasmic Reticulum ◽

Er Stress ◽

Unfolded Protein Response ◽

Diabetic Patients ◽

Β Cells ◽

Β Cell ◽

Unfolded Protein ◽

Islet Inflammation ◽

The Unfolded Protein Response ◽

Protein Response

Insulin-secreting pancreatic β-cells are extremely dependent on their endoplasmic reticulum (ER) to cope with the oscillatory requirement of secreted insulin to maintain normoglycemia. Insulin translation and folding rely greatly on the unfolded protein response (UPR), an array of three main signaling pathways designed to maintain ER homeostasis and limit ER stress. However, prolonged or excessive UPR activation triggers alternative molecular pathways that can lead to β-cell dysfunction and apoptosis. An increasing number of studies suggest a role of these pro-apoptotic UPR pathways in the downfall of β-cells observed in diabetic patients. Particularly, the past few years highlighted a cross talk between the UPR and inflammation in the context of both type 1 (T1D) and type 2 diabetes (T2D). In this article, we describe the recent advances in research regarding the interplay between ER stress, the UPR, and inflammation in the context of β-cell apoptosis leading to diabetes.

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The Unfolded Protein Response: A Pathway That Links Insulin Demand with β-Cell Failure and Diabetes

Endocrine Reviews ◽

10.1210/er.2007-0039 ◽

2008 ◽

Vol 29 (3) ◽

pp. 317-333 ◽

Cited By ~ 355

Author(s):

Donalyn Scheuner ◽

Randal J. Kaufman

Keyword(s):

Cell Death ◽

Protein Folding ◽

Unfolded Protein Response ◽

Secretory Pathway ◽

Cell Function ◽

Mrna Translation ◽

Β Cell ◽

Unfolded Protein ◽

The Unfolded Protein Response ◽

Protein Response

Abstract The endoplasmic reticulum (ER) is the entry site into the secretory pathway for newly synthesized proteins destined for the cell surface or released into the extracellular milieu. The study of protein folding and trafficking within the ER is an extremely active area of research that has provided novel insights into many disease processes. Cells have evolved mechanisms to modulate the capacity and quality of the ER protein-folding machinery to prevent the accumulation of unfolded or misfolded proteins. These signaling pathways are collectively termed the unfolded protein response (UPR). The UPR sensors signal a transcriptional response to expand the ER folding capacity, increase degredation of malfolded proteins, and limit the rate of mRNA translation to reduce the client protein load. Recent genetic and biochemical evidence in both humans and mice supports a requirement for the UPR to preserve ER homeostasis and prevent the β-cell failure that may be fundamental in the etiology of diabetes. Chronic or overwhelming ER stress stimuli associated with metabolic syndrome can disrupt protein folding in the ER, reduce insulin secretion, invoke oxidative stress, and activate cell death pathways. Therapeutic interventions to prevent polypeptide-misfolding, oxidative damage, and/or UPR-induced cell death have the potential to improve β-cell function and/or survival in the treatment of diabetes.

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The Pancreatic ß-cell Response to Secretory Demands and Adaption to Stress

Endocrinology ◽

10.1210/endocr/bqab173 ◽

2021 ◽

Vol 162 (11) ◽

Author(s):

Michael A Kalwat ◽

Donalyn Scheuner ◽

Karina Rodrigues-dos-Santos ◽

Decio L Eizirik ◽

Melanie H Cobb

Keyword(s):

Unfolded Protein Response ◽

Cell Function ◽

Protein Translation ◽

Insulin Production ◽

Β Cells ◽

Β Cell ◽

Compensatory Mechanisms ◽

Unfolded Protein ◽

The Unfolded Protein Response ◽

Protein Response

Abstract Pancreatic β cells dedicate much of their protein translation capacity to producing insulin to maintain glucose homeostasis. In response to increased secretory demand, β cells can compensate by increasing insulin production capability even in the face of protracted peripheral insulin resistance. The ability to amplify insulin secretion in response to hyperglycemia is a critical facet of β-cell function, and the exact mechanisms by which this occurs have been studied for decades. To adapt to the constant and fast-changing demands for insulin production, β cells use the unfolded protein response of the endoplasmic reticulum. Failure of these compensatory mechanisms contributes to both type 1 and 2 diabetes. Additionally, studies in which β cells are “rested” by reducing endogenous insulin demand have shown promise as a therapeutic strategy that could be applied more broadly. Here, we review recent findings in β cells pertaining to the metabolic amplifying pathway, the unfolded protein response, and potential advances in therapeutics based on β-cell rest.

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