title: Systematic proteomic analysis identifies β-site amyloid precursor protein cleaving enzyme 2 and 1 (BACE2 and BACE1) substrates in pancreatic β-cells.
abstract: 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 under 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 substrate 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 including two proteins of the seizure 6 protein family (SEZ6L and SEZ6L2). 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 a resource for therapeutic target and biomarker discoveries.
authors: Department of Biology, Institute of Molecular Health Sciences, ETH Zürich, CH-8093 Zürich, Switzerland.
authors: Ina
authors: I
authors: Stützer
authors: Nathalie
authors: N
authors: Selevsek
authors: Daria
authors: D
authors: Esterházy
authors: Alexander
authors: A
authors: Schmidt
authors: Ruedi
authors: R
authors: Aebersold
authors: Markus
authors: M
authors: Stoffel
mesh_terms: D053829:Amyloid Precursor Protein Secretases / Q000235:genetics / Q000378:metabolism*; D000818:Animals; D016282:Aspartic Acid Endopeptidases / Q000235:genetics / Q000378:metabolism*; D050417:Insulin-Secreting Cells / Q000166:cytology / Q000201:enzymology*; D051379:Mice; D018345:Mice, Knockout; D009419:Nerve Tissue Proteins / Q000235:genetics / Q000378:metabolism*; D040901:Proteomics / Q000379:methods
chemical_list: C509285:Bace2 protein, mouse; D009419:Nerve Tissue Proteins; C093131:Sez6 protein, mouse; D053829:Amyloid Precursor Protein Secretases; D016282:Aspartic Acid Endopeptidases; C509282:Bace1 protein, mouse