title: Intracellular trafficking of the amyloid β-protein precursor (APP) regulated by novel function of X11-like.
abstract: BACKGROUND
  Amyloid β (Aβ), a causative peptide of Alzheimer's disease, is generated by intracellular metabolism of amyloid β-protein precursor (APP). In general, mature APP (mAPP, N- and O-glycosylated form) is subject to successive cleavages by α- or β-, and γ-secretases in the late protein secretory pathway and/or at plasma membrane, while immature APP (imAPP, N-glycosylated form) locates in the early secretory pathway such as endoplasmic reticulum or cis-Golgi, in which imAPP is not subject to metabolic cleavages. X11-like (X11L) is a neural adaptor protein composed of a phosphotyrosine-binding (PTB) and two C-terminal PDZ domains. X11L suppresses amyloidogenic cleavage of mAPP by direct binding of X11L through its PTB domain, thereby generation of Aβ lowers. X11L expresses another function in the regulation of intracellular APP trafficking.
  
  
  METHODS
  In order to analyze novel function of X11L in intracellular trafficking of APP, we performed a functional dissection of X11L. Using cells expressing various domain-deleted X11L mutants, intracellular APP trafficking was examined along with analysis of APP metabolism including maturation (O-glycosylation), processing and localization of APP.
  
  
  CONCLUSIONS
  X11L accumulates imAPP into the early secretory pathway by mediation of its C-terminal PDZ domains, without being bound to imAPP directly. With this novel function, X11L suppresses overall APP metabolism and results in further suppression of Aβ generation. Interestingly some of the accumulated imAPP in the early secretory pathway are likely to appear on plasma membrane by unidentified mechanism. Trafficking of imAPP to plasma membrane is observed in other X11 family proteins, X11 and X11L2, but not in other APP-binding partners such as FE65 and JIP1. It is herein clear that respective functional domains of X11L regulate APP metabolism at multiple steps in intracellular protein secretory pathways.
authors.affiliation: Laboratory of Neuroscience, Graduate School of Pharmaceutical Science, Hokkaido University, Sapporo, Japan.
authors.forename: Yuhki
authors.initials: Y
authors.lastname: Saito
authors.forename: Mayu
authors.initials: M
authors.lastname: Akiyama
authors.forename: Yoichi
authors.initials: Y
authors.lastname: Araki
authors.forename: Akio
authors.initials: A
authors.lastname: Sumioka
authors.forename: Maki
authors.initials: M
authors.lastname: Shiono
authors.forename: Hidenori
authors.initials: H
authors.lastname: Taru
authors.forename: Tadashi
authors.initials: T
authors.lastname: Nakaya
authors.forename: Tohru
authors.initials: T
authors.lastname: Yamamoto
authors.forename: Toshiharu
authors.initials: T
authors.lastname: Suzuki
mesh_terms: D016564:Amyloid beta-Protein Precursor / Q000378:metabolism*; D000818:Animals; D020126:Brefeldin A / Q000494:pharmacology; D002352:Carrier Proteins / Q000737:chemistry / Q000378:metabolism*; D045744:Cell Line, Tumor; D002462:Cell Membrane / Q000187:drug effects / Q000378:metabolism; D042541:Intracellular Space / Q000187:drug effects / Q000378:metabolism*; D051379:Mice; D050505:Mutant Proteins / Q000378:metabolism; D011485:Protein Binding / Q000187:drug effects; D017434:Protein Structure, Tertiary; D021381:Protein Transport / Q000187:drug effects; D059748:Proteolysis / Q000187:drug effects; D013696:Temperature; D020761:rab1 GTP-Binding Proteins / Q000378:metabolism
chemical_list: D016564:Amyloid beta-Protein Precursor; D002352:Carrier Proteins; D050505:Mutant Proteins; D020126:Brefeldin A; D020761:rab1 GTP-Binding Proteins