Erschienen in:
The FEBS Journal, 281 (2014) 8, Seite 2074-2087
Sprache:
Englisch
DOI:
10.1111/febs.12763
ISSN:
1742-464X;
1742-4658
Entstehung:
Anmerkungen:
Beschreibung:
The β‐site amyloid precursor protein‐cleaving enzyme 1 (BACE1) is a protease that participates in the amyloidogenic cleavage of the Alzheimer amyloid precursor protein. Trafficking of BACE1 has been shown to be largely mediated by an acidic cluster dileucine motif in its cytoplasmic tail. This sorting signal functions both in endocytosis and endosomal sorting/recycling of BACE1 by providing a binding site for various sorting factors, such as the Golgi‐localizing γ‐ear containing ADP ribosylation factor binding (GGA) proteins that mediate BACE1 sorting within endosomes. Because flotillin‐1 has been suggested to bind to BACE1 cytoplasmic tail, we analyzed the role of flotillins in BACE1 sorting. We show that flotillin‐1 directly binds to the dileucine motif in the cytoplasmic tail of BACE1, whereas flotillin‐2 binding is mainly mediated by its interaction with flotillin‐1. Depletion of flotillins results in altered subcellular localization of BACE1 in endosomes and stabilization of BACE1 protein. Furthermore, amyloidogenic processing of Alzheimer amyloid precursor protein is increased. Flotillins compete with GGA proteins for binding to the dileucine motif in the BACE1 tail, suggesting that they play an important role in endosomal sorting of BACE1. The present study shows for the first time that flotillins are involved in endosomal sorting of BACE1. Because the endosomal localization of BACE1 affects its function as the β‐secretase by increasing amyloidogenic processing of the amyloid precursor protein, flotillins may play a novel role in Alzheimer's disease. The present study is the first to show that flotillins bind to a canonical sorting signal and influence the binding of endosomal sorting factors onto cargo tails.Structured digital abstract• BACE1 and flotillin-2 physically interact by proximity ligation assay (View interaction)• BACE1 and flotillin-1 physically interact by proximity ligation assay (View interaction)• BACE1 binds to flotillin-1 by pull down (View interaction)flotillin-2 physically interacts with BACE1 by anti bait coimmunoprecipitation (View interaction)