ArticleThe Journal of clinical investigation2024
Inhibition of the eukaryotic initiation factor-2α kinase PERK decreases risk of autoimmune diabetes in mice.
Article in The Journal of clinical investigation, 2024. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 17 papers.
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Who cites it
17 citing papers in PubMed.
- MDA5 and the integrated stress response control sex-specific type 1 diabetes onset in NOD mice.bioRxiv : the preprint server for biology · 2026Article
- Article
- Beyond bystanders: How β cell stress shapes the autoimmune response in T1D.Science translational medicine · 2026Review
- Messenger RNA delivery to islet β cells using conjugated lipid nanoparticles.Cell reports. Medicine · 2026Article
- Spatial proteomics in precision medicine: technologies, bioinformatics, and translational applications.Precision clinical medicine · 2026Review
- Calorie Restriction Upregulates Islet PD-L1 Signaling and Decreases the Risk of Autoimmune Diabetes Onset in NOD Mice.bioRxiv : the preprint server for biology · 2026Article
- Using animal models to decipher the role of polyamines in the pancreas and β Cell.Amino acids · 2026Review
- Stress-driven remodeling of antigen presentation and chemokine signaling in pancreatic β-cells: implications for type 1 diabetes.Frontiers in immunology · 2026Review
- Molecular and Inflammatory Etiologies of β-Cell Dysfunction in Type 1 Diabetes.Physiology (Bethesda, Md.) · 2025Review
- Insights into the molecular mechanism of neurological diseases and their pathophysiological responses.Archives of toxicology · 2025Review
- IL-1β priming triggers an adaptive stress response that enhances pancreatic β-cell resilience to subsequent cytotoxic inflammatory insult.Cell death & disease · 2025Article
- Diabetes mellitus and the key role of endoplasmic reticulum stress in pancreatic β cells.Nature reviews. Endocrinology · 2025Review
- Autoreactive T Cells and Cytokine Stress Drive β-Cell Senescence Entry and Accumulation in Type 1 Diabetes.Diabetes · 2025Article
- The integrated stress response promotes macrophage inflammation and migration in autoimmune diabetes.Cell communication and signaling : CCS · 2025Article
- Dysfunctional β-cell autophagy induces β-cell stress and enhances islet immunogenicity.Frontiers in immunology · 2025Article
- Harnessing beta-cell replication: advancing molecular insights to regenerative therapies in diabetes.Frontiers in endocrinology · 2025Review
- β-Cell gene expression stress signatures in types 1 and 2 diabetes.Journal of diabetes · 2024Article
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25 authors.
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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.
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