315-OR: The Membrane Protease Prostasin Promotes Insulin Secretion by Regulating the Epidermal Growth Factor Receptor Pathway

Abstract

Prostasin (PRSS8) is a serine protease that cleaves and regulates the activity of specific substrates. Epidermal growth factor receptor (EGFR) , which regulates insulin secretion and pancreatic β-cell proliferation, is activated via proteolytic shedding by PRSS8. In this study, we first found that PRSS8 is expressed in β-cells of mouse pancreatic islets. To clarify the molecular mechanisms of PRSS8-associated insulin secretion, we generated pancreatic β-cell-specific PRSS8 knockout (βKO) and PRSS8-overexpressing (βTG) mice. Overall, we observed glucose intolerance and decreased glucose-stimulated insulin secretion in the βKO mice compared to controls, whereas an increased response to glucose was observed in isolated islets from βTG mice. In vitro studies using MIN6 cells, we demonstrated that erlotinib, a specific inhibitor of EGFR, inhibits both EGF- and glucose-stimulated insulin secretion, and that glucose increases EGF secretion from β-cells. Following silencing of PRSS8, MIN6 cells showed lower levels of insulin secretion upon glucose stimulation, impaired EGFR signaling and lower expression levels of SNARE proteins. On the other hand, MIN6 cells overexpressing PRSS8 showed higher levels of insulin secretion at both the basal and glucose-stimulated insulin secretion, and higher phospho-EGFR levels. Furthermore, short-term exposure to glucose increased the expression level of endogenous PRSS8 protein in MIN6 cells, by blocking intracellular degradation. Our findings suggested that PRSS8 might be a blood glucose-dependent physiological modulator of insulin secretion via EGF-EGFR signaling in pancreatic β-cells. Disclosure T. Ishii: None. K. Uchimura: None. F. Furuya: None. Funding KAKENHI (19K17958 and 21K16367)