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

Abstract

BACE1 (β-site amyloidogenic cleavage of precursor protein-cleaving enzyme 1) is a β-secretase protein that plays a central role in the production of the β-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 β-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 β-subunit (IRβ) 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 IRβ trafficking and insulin signaling. In conclusion, BACE2 is hereby presented as an important enzyme in β-cell function.

Hypothesis review: are clathrin-mediated endocytosis and clathrin-dependent membrane and protein trafficking core pathophysiological processes in schizophrenia and bipolar disorder?

“…For example, CME has important roles in endocrine function 163 and the possibility that reported endocrine abnormalities in schizophrenia are a consequence of altered CME should be considered. Equally, cytoskeletal proteins are implicated in schizophrenia 22,26,18 and of these actin is particularly influenced by CME 164 .…”

Systematic Proteomic Analysis Identifies β-Site Amyloid Precursor Protein Cleaving Enzyme 2 and 1 (BACE2 and BACE1) Substrates in Pancreatic β-Cells

“…We have previously demonstrated that BACE2 is selectively expressed in pancreatic ␤-cells within human and mouse islets (8), while BACE1 has also been detected in ␣-cells (57). Given that the substrates determined here were initially mapped in a ␤-cell line and that an islet consists of 50 -80% of insulin-secreting ␤-cells (58), it is very likely that the ectodomains are released from ␤-cells, although in the case of BACE1, they may be cleaved simultaneously in ␣-cells.…”

Relevance of amyloid precursor-like protein 2 C-terminal fragments in pancreatic cancer cells

“…Two β-secretases, β-site APP-cleaving enzyme (BACE)1 and BACE2, have been implicated in the cleavage of APP family members (50,56). BACE2 is expressed in the pancreas (30) and specifically in pancreatic ductal cells (31), although other reports place BACE2 expression within islet cells (32). The relative contribution of BACE1 and BACE2 to the overall activity of β-secretase in pancreatic cancer cell lines and tissues remains an area of active research.…”

“…Recently, one BACE1 cleavage site in APLP2 was identified (23); however, BACE2 cut site(s) in APLP2 remain(s) unknown. Both BACE proteins have been reported in pancreatic tissue, but reports differ on BACE1 and BACE2 expression and activity in pancreatic ductal and acinar cells (22,23,27,29–32), which are cell types proposed to give rise to pancreatic cancer (33). …”