SUMOylation of Pdia3 exacerbates proinsulin misfolding and ER stress in pancreatic beta cells

SUMOylation has long been recognized to regulate multiple biological processes in pancreatic beta cells, but its impact on proinsulin disulfide maturation and endoplasmic reticulum (ER) stress remains elusive. Herein, we conducted comparative proteomic analyses of SUMOylated proteins in primary mouse/human islets following proinflammatory cytokine stimulation. Cytokine challenge rendered beta cells to undergo a SUMOylation turnover manifested by the changes of SUMOylation substrates and SUMOylation levels for multiple substrates. Our data support that SUMOylation may play a crucial role to regulate proinsulin misfolding and ER stress at least by targeting Protein Disulfide Isomerase a3 (Pdia3). SUMOylation regulates Pdia3 enzymatic activity, subcellular localization, and protein binding ability. Furthermore, SUMOylation of Pdia3 exacerbated proinsulin misfolding and ER stress, and repressed Stat3 activation. In contrast, disruption of Pdia3 SUMOylation markedly rescued the outcomes. Collectively, our study expands the understanding how SUMOylation regulates ER stress in beta cells, which shed light on developing potential strategies against beta cell dysfunction.