Intracellular trafficking of the amyloid β-protein precursor (APP) regulated by novel function of X11-like

Yuhki Saito, Mayu Akiyama, Yoichi Araki, Akio Sumioka, Maki Shiono, Hidenori Taru, Tadashi Nakaya, Tohru Yamamoto, Toshiharu Suzuki

Research output: Contribution to journalArticle

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. Methodology: 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.

Original languageEnglish (US)
Article numbere22108
JournalPLoS One
Volume6
Issue number7
DOIs
StatePublished - 2011
Externally publishedYes

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Amyloid beta-Protein Precursor
amyloid
Secretory Pathway
proteins
Metabolism
Cell membranes
PDZ Domains
Phosphotyrosine
Cell Membrane
Protein Transport
metabolism
plasma membrane
Proteins
Glycosylation
Dissection
Amyloid Precursor Protein Secretases
Amyloid
Protein Binding
Endoplasmic Reticulum
Alzheimer Disease

ASJC Scopus subject areas

  • Agricultural and Biological Sciences(all)
  • Biochemistry, Genetics and Molecular Biology(all)
  • Medicine(all)

Cite this

Intracellular trafficking of the amyloid β-protein precursor (APP) regulated by novel function of X11-like. / Saito, Yuhki; Akiyama, Mayu; Araki, Yoichi; Sumioka, Akio; Shiono, Maki; Taru, Hidenori; Nakaya, Tadashi; Yamamoto, Tohru; Suzuki, Toshiharu.

In: PLoS One, Vol. 6, No. 7, e22108, 2011.

Research output: Contribution to journalArticle

Saito, Y, Akiyama, M, Araki, Y, Sumioka, A, Shiono, M, Taru, H, Nakaya, T, Yamamoto, T & Suzuki, T 2011, 'Intracellular trafficking of the amyloid β-protein precursor (APP) regulated by novel function of X11-like', PLoS One, vol. 6, no. 7, e22108. https://doi.org/10.1371/journal.pone.0022108
Saito, Yuhki ; Akiyama, Mayu ; Araki, Yoichi ; Sumioka, Akio ; Shiono, Maki ; Taru, Hidenori ; Nakaya, Tadashi ; Yamamoto, Tohru ; Suzuki, Toshiharu. / Intracellular trafficking of the amyloid β-protein precursor (APP) regulated by novel function of X11-like. In: PLoS One. 2011 ; Vol. 6, No. 7.
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AU - Akiyama, Mayu

AU - Araki, Yoichi

AU - Sumioka, Akio

AU - Shiono, Maki

AU - Taru, Hidenori

AU - Nakaya, Tadashi

AU - Yamamoto, Tohru

AU - Suzuki, Toshiharu

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