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ResearchIn-Press PreviewEndocrinology
Open Access | 10.1172/JCI176136
1Medicine, The University of Chicago, Chicago, United States of America
2Medicine, The Univeristy of Chicago, Chicago, United States of America
3HiberCell, New York, United States of America
4ULB Center for Diabetes Research, Universite Libre de Bruxelles, Brussels, Belgium
5Biological Sciences Division, Pacific Northwest National Laboratory, Richland, United States of America
6Pathology, The University of Chicago, Chicago, United States of America
7Pediatrics, Indiana University School of Medicine, Indianapolis, United States of America
8Biochemistry and Molecular Biology, Indiana University School of Medicine, Indianapolis, United States of America
9Biological Sciences Division, Pacific Northwest National Laboratory, RIchland, United States of America
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Published June 18, 2024 - More info
Preventing the onset of autoimmune type 1 diabetes (T1D) is feasible through pharmacological interventions that target molecular stress-responsive mechanisms. Cellular stresses, such as nutrient deficiency, viral infection, or unfolded proteins, trigger the integrated stress response (ISR), which curtails protein synthesis by phosphorylating eIF2α. In T1D, maladaptive unfolded protein response (UPR) in insulin-producing beta cells renders these cells susceptible to autoimmunity. We found that inhibition of the eIF2α kinase PERK, a common component of the UPR and ISR, reversed the mRNA translation block in stressed human islets and delayed the onset of diabetes, reduced islet inflammation, and preserved β cell mass in T1D-susceptible mice. Single-cell RNA sequencing of islets from PERK-inhibited mice showed reductions in the UPR and PERK signaling pathways and alterations in antigen processing and presentation pathways in β cells. Spatial proteomics of islets from these mice showed an increase in the immune checkpoint protein PD-L1 in β cells. Golgi membrane protein 1, whose levels increased following PERK inhibition in human islets and EndoC-βH1 human β cells, interacted with and stabilized PD-L1. Collectively, our studies show that PERK activity enhances β cell immunogenicity, and inhibition of PERK may offer a strategy to prevent or delay the development of T1D.