Suppression of the Integrated Stress Response in Islet β Cells Decreases Risk of Autoimmune Diabetes

Abstract

ABSTRACTPrevention or delay of autoimmune type 1 diabetes (T1D) onset is possible if molecular triggering events can be pharmacologically targeted. The integrated stress response (ISR) is activated during cellular stress to temporarily halt protein production and redirect energy towards cellular survival. We hypothesized that activity of the ISR in the insulin-producing β cell during T1D becomes maladaptive and renders the cell prone to autoimmunity. We show that suppression of the ISR by using a novel inhibitor of the kinase PERK reverses the translation initiation 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 unfolded protein response and PERK signaling pathways as well as alterations in antigen processing and presentation pathways in β cells. Spatial proteomics analysis of islets from these mice show a post-transcriptional increase in the immune checkpoint protein PD-L1 in β cells. Golgi membrane protein 1, whose levels increase following ISR inhibition in human islets and EndoC-βH1 human β cells, interacts with and post-transcriptionally stabilizes PD-L1. Collectively, our studies show that the ISR, mediated by PERK, enhances β cell immunogenicity, and inhibition of PERK may offer a strategy to prevent or delay the development of T1D.