Systematic proteomic analysis identifies beta-site amyloid precursor protein cleaving enzyme 2 and 1 (BACE2 and BACE1) substrates in pancreatic beta-cells

Expansion of functional islet β-cell mass is a physiological process to compensate for increased insulin demand. Deficiency or pharmacological inhibition of the plasma membrane protease BACE2 enhances pancreatic β-cell function and proliferation and therefore BACE2 is a putative target for the therapeutic intervention in conditions of β-cell loss and dysfunction. To gain a molecular understanding of BACE2 function we performed a systematic and quantitative proteomic analysis to map the natural sub-strate repertoire of BACE2 and its homologue BACE1 in β-cells. Loss-and gain-of-function studies of in vitro and in vivo models identified specific and functionally heterogeneous targets. Our analysis revealed non-redundant roles of BACE1/2 in ectodomain shedding with BACE1 regulating a broader and BACE2 a more distinct set of β-cell-enriched substrates. Lastly, our study provides insights into the global β-cell sheddome and secretome, an important prerequisite to uncover novel mechanisms contributing to β-cell homeostasis and to offer a resource for therapeutic target and biomarker discoveries.