2. Academic Validation
  3. Inhibition of the Eukaryotic Initiation Factor-2-α Kinase PERK Decreases Risk of Autoimmune Diabetes in Mice

Inhibition of the Eukaryotic Initiation Factor-2-α Kinase PERK Decreases Risk of Autoimmune Diabetes in Mice

  • bioRxiv. 2024 Jun 3:2023.10.06.561126. doi: 10.1101/2023.10.06.561126.
Charanya Muralidharan 1,  Fei Huang 1,  Jacob R Enriquez 1,  Jiayi E Wang 1,  Jennifer B Nelson 1,  Titli Nargis 1,  Sarah C May 1,  Advaita Chakraborty 1,  Kayla T Figatner 1,  Svetlana Navitskaya 1,  Cara M Anderson 1,  Veronica Calvo 2,  David Surguladze 2,  Mark J Mulvihill 2,  Xiaoyan Yi 3,  Soumyadeep Sarkar 4,  Scott A Oakes 5,  Bobbie-Jo M Webb-Robertson 4,  Emily K Sims 6,  Kirk A Staschke 7,  Decio L Eizirik 3,  Ernesto S Nakayasu 4,  Michael E Stokes 2,  Sarah A Tersey 1,  Raghavendra G Mirmira 1
Affiliations

Affiliations

  • 1 Department of Medicine and the Kovler Diabetes Center, The University of Chicago, Chicago, IL, USA.
  • 2 HiberCell Inc., New York, NY, USA.
  • 3 ULB Center for Diabetes Research, Université Libre de Bruxelles, Brussels, Belgium.
  • 4 Biological Sciences Division, Pacific Northwest National Laboratory, Richland, WA, USA.
  • 5 Department of Pathology, The University of Chicago, Chicago, IL, USA.
  • 6 Department of Pediatrics, Center for Diabetes and Metabolic Diseases, and the Wells Center for Pediatric Research, Indiana University School of Medicine, Indianapolis, IN.
  • 7 Department of Biochemistry and Molecular Biology and the Melvin and Bren Simon Cancer Center, Indiana University School of Medicine, Indianapolis, IN, USA.
PMID: 38895427 DOI: 10.1101/2023.10.06.561126
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 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.

Keywords

Unfolded protein response; integrated stress response; islet; mRNA translation; type 1 diabetes.

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