BACE2 plays a role in the insulin receptor trafficking in pancreatic β-cells

Casas S, Casini P, Piquer S, Altirriba J, Soty M, Cadavez L, Gomis R, Novials A. BACE2 plays a role in the insulin receptor trafficking in pancreatic beta-cells. Am J Physiol Endocrinol Metab 299: E1087-E1095, 2010. First published October 13, 2010; doi:10.1152/ajpendo.00420.2010.-BACE1 (beta-site amyloidogenic cleavage of precursor protein-cleaving enzyme 1) is a beta-secretase protein that plays a central role in the production of the beta-amyloid peptide in the brain and is thought to be involved in the Alzheimer's pathogenesis. In type 2 diabetes, amyloid deposition within the pancreatic islets is a pathophysiological hallmark, making crucial the study in the pancreas of BACE1 and its homologous BACE2 to understand the pathological mechanisms of this disease. The objectives of the present study were to characterize the localization of BACE proteins in human pancreas and determine their function. High levels of BACE enzymatic activity were detected in human pancreas. In normal human pancreas, BACE1 was observed in endocrine as well as in exocrine pancreas, whereas BACE2 expression was restricted to beta-cells. Intracellular analysis using immunofluorescence showed colocalization of BACE1 with insulin and BACE2 with clathrin-coated vesicles of the plasma membrane in MIN6 cells. When BACE1 and -2 were pharmacologically inhibited, BACE1 localization was not altered, whereas BACE2 content in clathrin-coated vesicles was increased. Insulin internalization rate was reduced, insulin receptor beta-subunit (IR beta) expression was decreased at the plasma membrane and increased in the Golgi apparatus, and a significant reduction in insulin gene expression was detected. Similar results were obtained after specific BACE2 silencing in MIN6 cells. All these data point to a role for BACE2 in the IR beta trafficking and insulin signaling. In conclusion, BACE2 is hereby presented as an important enzyme in beta-cell function.