title: BRI2 interacts with BACE1 and regulates its cellular levels by promoting its degradation and reducing its mRNA levels.
abstract: BRI2, a protein mutated in Familial British and Familial Danish Dementias, interacts with Amyloid Precursor Protein (APP) and reduces the levels of secreted APPβ (sAPPβ), which derives from APP cleavage by β-secretase (BACE1). Exploring the mechanisms of this effect, we obtained data that BRI2 decreases the cellular levels of BACE1 thus reducing the β-cleavage of APP. Deletion of N-terminal cytoplasmic or C-terminal extracellular sequences of BRI2 neither affected its interaction with BACE1 or APP (Fotinopoulou et al., 2005) nor the reduction in the levels of BACE1 and sAPPβ. These results suggest that BRI2 may prevent access of BACE1 to APP and the BRI2/BACE1 interaction may mediate the reduction in BACE1 levels. In support, BRI2 expression induced lysosomal but not proteasomal degradation of BACE1. In parallel, BRI2 expression was also found to reduce BACE1 mRNA levels by 50%. This study adds novel information regarding the mechanism by which BRI2 affects APP processing and BACE1 levels.
authors.affiliation: Division of Animal and Human Physiology, Department of Biology, National & Kapodistrian University of Athens, 157 84 Panepistimiopolis, Ilisia, Athens, Greece.
authors.forename: Maria
authors.initials: M
authors.lastname: Tsachaki
authors.forename: Angeliki
authors.initials: A
authors.lastname: Fotinopoulou
authors.forename: Nefeli
authors.initials: N
authors.lastname: Slavi
authors.forename: Vasiliki
authors.initials: V
authors.lastname: Zarkou
authors.forename: Jorge
authors.initials: J
authors.lastname: Ghiso
authors.forename: Spiros
authors.initials: S
authors.lastname: Efthimiopoulos
mesh_terms: D048868:Adaptor Proteins, Signal Transducing; D053829:Amyloid Precursor Protein Secretases / Q000235:genetics* / Q000378:metabolism*; D016564:Amyloid beta-Protein Precursor / Q000235:genetics / Q000378:metabolism; D016282:Aspartic Acid Endopeptidases / Q000235:genetics* / Q000378:metabolism*; D045604:Extracellular Fluid / Q000378:metabolism*; D005786:Gene Expression Regulation / Q000235:genetics; D057809:HEK293 Cells; D006801:Humans; D047468:Immunoprecipitation; D008562:Membrane Glycoproteins / Q000235:genetics* / Q000378:metabolism*; D018613:Microscopy, Confocal; D012333:RNA, Messenger / Q000378:metabolism*; D014162:Transfection
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D016564:Amyloid beta-Protein Precursor; C120083:ITM2B protein, human; D008562:Membrane Glycoproteins; D012333:RNA, Messenger; D053829:Amyloid Precursor Protein Secretases; D016282:Aspartic Acid Endopeptidases; C509280:BACE1 protein, human