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Diabetes and Vascular Disease

ORF14-06 - S-Palmitoylation in Interferon-Mediated STAT Signaling and Β Cell Dysfunction in Type 1 Diabetes

Saturday, June 13, 2026
2:40 PM - 2:55 PM CT
Location: Room W181AB
Disclosure(s):
Ernesto S. Nakayasu, PhD: No financial relationships to disclose
Sarah A. Tersey, PhD: No financial relationships to disclose

The recent successes of JAK inhibitors in type 1 diabetes (T1D) clinical trials emphasize the pathogenic nature of interferon signaling in T1D. Canonical interferon signaling activates interferon receptors, leading to STAT protein phosphorylation. STAT proteins undergo S-palmitoylation by palmitoyltransferases, enabling membrane tethering and phosphorylation by JAK proteins. Depalmitoylation then allows phosphorylated STAT proteins to dimerize and enter the nucleus, where they upregulate interferon-responsive genes. Interestingly, a recent preprint study performed lipidomic profiling on plasma samples from TEDDY study participants and found that palmitate (C16:0), the substrate for palmitoylation, was significantly increased at seroconversion. In T1D, it is unknown how palmitoyltransferases (DHHC family of enzymes) and depalmitoylases regulate STAT responses in β cells and how this regulation affects T1D outcomes. Gene Set Enrichment Analysis (GSEA) was performed on the β cell clusters on sc-RNA sequencing data from control, Aab+, and T1D samples in the Human Pancreas Analysis Program (HPAP). MIN6 mouse β cells were treated with palmitoylation inhibitor 2-Bromopalmitate (50μM 2BP) or depalmitoylase inhibitor ML349 (50μM) for 24 h, followed by IFNγ co-treatment for 24 h. At the end of the treatments, palmitoylation levels using Acyl-biotin exchange assay and gene expression analysis using RNAseq were performed. STAT1 regulation was evaluated in EndoC-βH1 human β cells after treating cells with 2BP±IFNγ for 24 h. Pre-diabetic NOD mice were intra-peritoneally injected with 20mg/kg 2BP for 5 days a week for four weeks (6-10 weeks of age), and insulitis severity was assessed. GSEA analysis of HPAP sc-RNAseq data revealed significant enrichment of palmitoylation and depalmitoylation genes in β cells from Aab+ and T1D donors compared to controls. This suggests upregulation of these pathways during pre-diabetic and diabetic stages. MIN6 experiments indicated an interferon-mediated enrichment of palmitoylation, which was strikingly reduced through the inhibition of the palmitoyl cycle (palmitoylation-depalmitoylation events). RNAseq analysis of MIN6 cells for significantly different interferon-stimulated genes (ISGs) revealed an overall decrease in ISGs in 2BP-treated samples. In EndoC-βH1 cells, while IFNγ increased STAT1 levels as expected, inhibition of palmitoylation significantly decreased STAT1 levels. Additionally, assessment of insulitis showed that the degree of mononuclear infiltrates was reduced in islets of 2BP injected NOD mice, portending a favorable diabetes outcome. Our data demonstrate that palmitoylation and interferon signaling pathways are intricately linked to β cell dysfunction in T1D, providing new insights into the molecular mechanisms driving T1D pathogenesis.