Abstract
The high rate of protein synthesis in beta-cells renders them susceptible to endoplasmic reticulum (ER) stress, a condition that can be aggravated by additional imbalances in ER homeostasis and could potentially contribute to the pathogenesis of type-1 and type-2 diabetes. Islet-specific glucose-6-phosphatase catalytic subunit-related protein (IGRP) is an ER-resident protein that is specifically expressed in pancreatic beta-cells and is a major target of diabetogenic CD8(+) T cell responses in non-obese diabetic (NOD) mice. We produced transgenic mice expressing human IGRP (hIGRP) under the control of rat insulin promoter (RIP) to study epitopes in hIGRP capable of driving diabetogenic human leukocyte antigen (HLA)-restricted CD8(+) T-cell responses in hIGRP/HLA transgenic NOD mice. Surprisingly, we found that 3 out of 14 lines expressing RIP-hIGRP in a non-T1D-prone genetic background developed a form of early-onset diabetes that was dissociated from autoimmune inflammation of pancreatic islets. We show that diabetes in these 3 lines resulted from increased rates of beta-cell death because of ER stress. We hypothesize that IGRP compounds the viability of beta-cells undergoing ER stress by generating unfolded proteins in the ER lumen, and that IGRP's location in the ER accounts, in part, for its exquisite immunogenicity in T1D-prone genetic backgrounds.
Highlights
The high rate of protein synthesis in β-cells renders them susceptible to endoplasmic reticulum (ER) stress, a condition that can be aggravated by additional imbalances in ER homeostasis and could potentially contribute to the pathogenesis of type 1 and type 2 diabetes
Islet-specific glucose6-phosphatase catalytic subunit-related protein (IGRP) is an ER-resident protein that is expressed in pancreatic β-cells and is a major target of diabetogenic CD8+ T cell responses in non-obese diabetic (NOD) mice
We show that overexpression of IGRP in pancreatic β-cells can induce a form of early onset non-immune-mediated diabetes that is associated with increased ER stress and β
Summary
The high rate of protein synthesis in β-cells renders them susceptible to endoplasmic reticulum (ER) stress, a condition that can be aggravated by additional imbalances in ER homeostasis and could potentially contribute to the pathogenesis of type 1 and type 2 diabetes. ER stress is a condition in which cellular insults like oxidative stress, aberrant Ca2+ regulation or protein overexpression promote inappropriate folding of proteins in the ER This leads to a cellular response, coined as the unfolded protein response (UPR), which involves both the upregulation of ER chaperones as a way to enhance the protein folding capacity of the ER and an attenuation of new protein synthesis. This response increases the ‘ER-associated degradation’ (ERAD) of misfolded proteins and promotes cell death [4]
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