Inhibition of the eukaryotic initiation factor-2α kinase PERK decreases risk of autoimmune diabetes in mice
Charanya Muralidharan, … , Sarah A. Tersey, Raghavendra G. Mirmira
Charanya Muralidharan, … , Sarah A. Tersey, Raghavendra G. Mirmira
Published June 18, 2024
Citation Information: J Clin Invest. 2024;134(16):e176136. https://doi.org/10.1172/JCI176136.
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Inhibition of the eukaryotic initiation factor-2α kinase PERK decreases risk of autoimmune diabetes in mice

Abstract

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-2α (eIF2α). In T1D, maladaptive unfolded protein response (UPR) in insulin-producing β cells renders these cells susceptible to autoimmunity. We found that inhibition of the eIF2α 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 β 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 β cells. Spatial proteomics of islets from these mice showed an increase in the immune checkpoint protein programmed death-ligand 1 (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 that inhibition of PERK may offer a strategy for preventing or delaying the development of T1D.

Authors

Charanya Muralidharan, Fei Huang, Jacob R. Enriquez, Jiayi E. Wang, Jennifer B. Nelson, Titli Nargis, Sarah C. May, Advaita Chakraborty, Kayla T. Figatner, Svetlana Navitskaya, Cara M. Anderson, Veronica Calvo, David Surguladze, Mark J. Mulvihill, Xiaoyan Yi, Soumyadeep Sarkar, Scott A. Oakes, Bobbie-Jo M. Webb-Robertson, Emily K. Sims, Kirk A. Staschke, Decio L. Eizirik, Ernesto S. Nakayasu, Michael E. Stokes, Sarah A. Tersey, Raghavendra G. Mirmira

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Figure 2

PERK inhibition delays autoimmune diabetes in NOD mice.

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PERK inhibition delays autoimmune diabetes in NOD mice. Prediabetic fema...
Prediabetic female NOD mice (6 weeks of age) were treated with varying doses of HC-5770 or ISRIB. (A) Experimental design for diabetes incidence study. (B) Diabetes incidence. n = 20 mice per group (Mantel-Cox). (C) Representative H&E stain of pancreata from nondiabetic mice at 25 weeks of age that were treated between 6 and 10 weeks of age. A, acinar; I, islet. Scale bars: 50 μm. (D) Experimental design mechanistic studies. (E) Representative images of pancreata from NOD mice following 2 weeks of HC-5770 administration (6 mg/kg) stained for insulin (brown) and counterstained with hematoxylin (blue). Scale bars: 500 μm. (F) β Cell mass of mice treated with HC-5770 (6 mg/kg) for 2 weeks; n = 4–5 mice per group (ANOVA). (G) Representative images of pancreata from NOD mice following 2 weeks of HC-5770 administration immunostained as indicated. Arrows indicate regions of insulitis. Scale bars: 50 μm. (H) Average insulitis score of mice treated with varying doses of HC-5770 for 2 weeks; n = 4–5 mice per group. NB: these data are replicated in Supplemental Figure 2F for comparative purposes (ANOVA). (I) Experimental design. (J) Representative images of pancreata from NOD mice following 2 weeks of ISRIB administration stained as indicated. Scale bars: 500 μm. (K) β Cell mass of mice treated with ISRIB for 2 weeks; n = 4–5 mice per group (ANOVA). (L) Representative images of pancreata from NOD mice following 2 weeks of ISRIB administration immunostained as indicated; arrows indicate regions of insulitis. Scale bars: 50 μm. (M) Average insulitis score of mice treated with varying doses of ISRIB for 2 weeks; n = 4–5 mice per group (ANOVA). Data are presented as mean ± SEM.