Protein post translational modifications and diabetes. Pro-inflammatory cytokines reshape lysin acetylome of rat clonal β cells and human pancreatic islets.

Type I diabetes mellitus (T1DM) is characterized by insulin deficiency due to β cells death caused by inflammation and immune reaction. Pro-inflammatory cytokines play a key role in T1DM pathogenesis by activating the pro-apoptotic pathway. Cytokine-activated NF-κB and STAT1 signalling also leads to oxidative stress and triggers the antigen presentation pathway. Stressful stimuli and self-defence responses combined cause mitochondrial dysfunction and endoplasmic reticulum (ER) stress, which progress to β cell functional impairments and death. Some molecular mechanisms involved in the progressive loss of functions are still unknown. In this contest, a study, which analyses proteomic changes of β cells upon cytokine prolonged exposure, can be useful. The global effects of pro-inflammatory cytokines, IL-1β and INF-γ, on protein expression, Nε-acetylation, and thermal stability was studied using different proteomic approaches and β cell models (rat INS-1E cells and human pancreatic islets). At first, the impact of cytokines on β cell insulin secretion, survival and apoptosis activation was examined to confirm functional impairment. Differential expression proteomics showed that cytokines dysregulated the expression of many proteins, which are components of pathways involved in T1DM pathogenesis. The study of protein lysine acetylome highlighted 83 and 242 differentially modified proteins in human islets and INS-1E cells, respectively. Most proteins are related to metabolic, mitochondrial dysfunction, inflammation, and insulin secretion pathways. In INS-1E cells, an analysis of Proteome Integral Solubility Alteration (PISA) was also performed. This technique allowed to identify 504 proteins, which thermal stability was modified by cell exposure to cytokines. Many of these proteins participate to protein synthesis, protein trafficking, and antigen presentation or are directly involved in mediating cytokine effects. Overall, this multi-level proteomic analysis unveiled new potential players of cytokine-induced β cells dysfunction.