1. Inhibition of the eukaryotic initiation factor-2[alpha] kinase PERK decreases risk of autoimmune diabetes in mice
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Muralidharan, Charanya, Huang, Fei, Enriquez, Jacob R., Wang, Jiayi E., Nelson, Jennifer B., Nargis, Titli, May, Sarah C., Chakraborty, Advaita, Figatner, Kayla T., Navitskaya, Svetlana, Anderson, Cara M., Calvo, Veronica, Surguladze, David, Mulvihill, Mark J., Yi, Xiaoyan, Sarkar, Soumyadeep, Oakes, Scott A., Webb-Robertson, Bobbie-Jo M., Sims, Emily K., Staschke, Kirk A., Eizirik, Decio L., Nakayasu, Ernesto S., Stokes, Michael E., Tersey, Sarah A., and Mirmira, Raghavendra G.
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Ligands (Biochemistry) -- Health aspects ,Type 1 diabetes -- Diagnosis -- Care and treatment ,Phosphotransferases -- Health aspects ,Stress (Physiology) -- Health aspects - 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-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 [...]
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- 2024
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