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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 eukaryotic translation initiation factor-2[alpha] (eIF2[alpha]). In T1D, maladaptive unfolded protein response (UPR) in insulin-producing [beta] cells renders these cells susceptible to autoimmunity. We found that inhibition of the eIF2a kinase PKR-like ER 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 [beta] cell mass in T1D-susceptible mice. Single-cell RNA-Seq of islets from PERK-inhibited mice showed reductions in the UPR and PERK signaling pathways and alterations in antigen-processing and presentation pathways in p cells. Spatial proteomics of islets from these mice showed an increase in the immune checkpoint protein programmed death-ligand 1 (PD-L1) in [beta] cells. Golgi membrane protein 1, whose levels increased following PERK inhibition in human islets and EndoC-[beta]H1 human [beta] cells, interacted with and stabilized PD-L1. Collectively, our studies show that PERK activity enhances [beta] cell immunogenicity and that inhibition of PERK may offer a strategy for preventing or delaying the development of T1D., Introduction Type 1 diabetes (T1D) is a disorder of glucose homeostasis that results from the autoimmune destruction of insulin-producing islet [beta] cells. The importance of the immune system in initiating [...]

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 β cells renders these cells susceptible to autoimmunity. We show that inhibition of the eIF2α kinase PERK, a common component of the UPR and ISR, reverses the mRNA translation block in stressed human islets and delays the onset of diabetes, reduces islet inflammation, and preserves β cell mass in T1D-susceptible mice. Single-cell RNA sequencing of islets from PERK-inhibited mice shows 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 shows an increase in the immune checkpoint protein PD-L1 in β cells. Golgi membrane protein 1, whose levels increase following PERK inhibition in human islets and EndoC-βH1 human β cells, interacts with and stabilizes 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., Competing Interests: DECLARATION OF INTERESTS VC, MES, DS, and MJM are employees of HiberCell, Inc. SAT, RGM, and HiberCell, Inc. have filed a provisional patent on compounds to inhibit PERK in type 1 diabetes. SAT and RGM received an investigator-initiated award from HiberCell, Inc. for use of PERK inhibitors in this study. KAS is a consultant for and has received research support from HiberCell, Inc. SAO is a co-founder, equity holder, and consultant for OptiKIRA, LLC.