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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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Research Article Endocrinology Article has an altmetric score of 2

Inhibition of the eukaryotic initiation factor-2α kinase PERK decreases risk of autoimmune diabetes in mice

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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 4

GOLM1 stabilizes PD-L1.

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GOLM1 stabilizes PD-L1.
(A) PD-L1 and GOLM1 protein levels were identifi...
(A) PD-L1 and GOLM1 protein levels were identified using proteomics of EndoC-βH1 human β cells treated with or without proinflammatory cytokines; n = 3 biological replicates. t test. (B) Representative immunoblot analysis of PD-L1 and GOLM1 from EndoC-βH1 cells treated with or without PIC, HC-5770, and ISRIB (left panel) with quantification of PD-L1 levels (middle panel) and GOLM1 levels (right panel); n = 3 biological replicates (ANOVA). (C and D) Relative CD274 and GOLM1 mRNA levels by quantitative reverse-transcriptase PCR (RT-PCR) normalized to ACTB in EndoC-βH1 cells treated as indicated; n = 4–7 biological replicates (ANOVA). (E) Relative GOLM1 RNA levels normalized to ACTB in EndoC-βH1 cells treated as indicated; n = 3 biological replicates (ANOVA). (F) Representative immunoblot analysis of PD-L1 and GOLM1 in EndoC-βH1 cells treated as indicated (left panel) with quantification of PD-L1 levels (right panel); n = 3 biological replicates (ANOVA). (G) Relative CD274 mRNA levels by quantitative RT-PCR normalized to ACTB in EndoC-βH1 cells treated as indicated; n = 3 biological replicates (ANOVA). (H) Representative immunoblot analysis of HLA-I from EndoC-βH1 cells treated as indicated (left panel) with quantification of HLA-I levels (right panel); n = 3 biological replicates (ANOVA). (I) Relative HLA-I mRNA levels by quantitative RT-PCR normalized to ACTB in EndoC-βH1 cells treated as indicated; n = 3 biological replicates (ANOVA). (J) Representative immunoblot analysis of PD-L1 in EndoC-βH1 cells treated as indicated. (K) Immunoblot analysis of ubiquitin following immunoprecipitation for PD-L1 from HEK-293 cells treated as indicated. (L) Immunoblot analysis for GOLM1 following immunoprecipitation for PD-L1 from HEK-293 cells. Data are presented as mean ± SEM.

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