Membrane protease prostasin promotes insulin secretion by regulating the epidermal growth factor receptor pathway

• Published in: Scientific reports Vol. 13; no. 1; pp. 9086 - 13
• Main Authors: Ishii, Toshihisa, Miyasato, Yoshikazu, Ichijo, Masashi, Uchimura, Kohei, Furuya, Fumihiko
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 05.06.2023; Nature Publishing Group; Nature Portfolio
• Subjects: 631/337; 631/80; Beta cells; Cell proliferation; Epidermal growth factor; Epidermal growth factor receptors; Glucose; Glucose tolerance; Humanities and Social Sciences; Inhibitor drugs; Insulin; Insulin secretion; Intolerance; multidisciplinary; Pancreas; Proteolysis; Science; Science (multidisciplinary); Secretion; Serine proteinase; Signal transduction
• DOI: 10.1038/s41598-023-36326-7
• ISSN: 2045-2322

Prostasin (PRSS8) is a serine protease that metabolizes and moderates the effect of specific substrates. Epidermal growth factor receptor (EGFR), which modulates insulin secretion and pancreatic β-cell proliferation, is regulated via proteolytic shedding by PRSS8. We first detected PRSS8 expression in β-cells of pancreatic islets of mice. To better understand the molecular processes involved in PRSS8-associated insulin secretion, pancreatic β-cell-specific PRSS8 knockout (βKO) and PRSS8-overexpressing (βTG) male mice were generated. We found that glucose intolerance and reduction in glucose-stimulated insulin secretion developed in βKO mice compared with the control subjects. A higher response to glucose was noted in islets retrieved from βTG mice. Erlotinib, a specific blocker of EGFR, blocks EGF- and glucose-stimulated secretion of insulin among MIN6 cells, and glucose improves EGF release from β-cells. After silencing PRSS8 in MIN6 cells, glucose-stimulated insulin secretion decreased, and EGFR signaling was impaired. Conversely, overexpression of PRSS8 in MIN6 cells induced higher concentrations of both basal and glucose-stimulated insulin secretion and increased phospho-EGFR concentrations. Furthermore, short-term exposure to glucose improved the concentration of endogenous PRSS8 in MIN6 cells through inhibition of intracellular degradation. These findings suggest that PRSS8 is involved in glucose-dependent physiological regulation of insulin secretion via the EGF–EGFR signaling pathway in pancreatic β-cells.