Inhibition of the Eukaryotic Initiation Factor-2-a Kinase PERK Decreases Risk of Autoimmune Diabetes in Mice
Prevention 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 halt protein production and redirect energy towards cellular survival temporarily. We hypothesized that the activity of the ISR in the insulin-producing ß 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 ß 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 and alterations in antigen processing and presentation pathways in ß cells. Spatial proteomics analysis of islets from these mice shows a post-transcriptional increase in the immune checkpoint protein PD-L1 in ß cells. Golgi membrane protein 1, whose levels increase following ISR inhibition in human islets and EndoC-ßH1 human ß cells, interacts with and post-transcriptionally stabilizes PD-L1. Collectively, our studies show that the ISR, mediated by PERK, enhances ß cell immunogenicity, and inhibition of PERK may offer a strategy to prevent or delay the development of T1D. Overall design: Female NOD mice were oral-gavaged with vehicle or 6 mg/kg HC-5770 (PERK inhibitor) for 2 weeks (6-8 weeks of age). At the end of the treatment, mouse islets were isolated following Stull et al., 2012 and samples were submitted for scRNAseq (n=3 biological replicates per group).