Ubiquilin-1 regulates amyloid precursor protein maturation and degradation by stimulating K63-linked polyubiquitination of lysine 688

Amina El Ayadi, Emily S. Stieren, José M. Barral, Darren Boehning

    Research output: Contribution to journalArticle

    49 Citations (Scopus)

    Abstract

    The pathogenesis of Alzheimer's disease (AD) is associated with proteolytic processing of the amyloid precursor protein (APP) to an amyloidogenic peptide termed Aβ. Although mutations in APP and the secretase enzymes that mediate its processing are known to result in familial forms of AD, the mechanisms underlying the more common sporadic forms of the disease are still unclear. Evidence suggests that the susceptibility of APP to amyloidogenic processing is related to its intracellular localization, and that secretase-independent degradation may prevent the formation of cytotoxic peptide fragments. Recently, single nucleotide polymorphisms in the UBQLN1 gene have been linked to late-onset AD, and its protein product, ubiquilin-1, may regulate the maturation of full-length APP. Here we show that ubiquilin-1 inhibits the maturation of APP by sequestering it in the early secretory pathway, primarily within the Golgi apparatus. This sequestration significantly delayed the proteolytic processing of APP by secretases and the proteasome. These effects were mediated by ubiquilin-1-stimulated K63-linked polyubiquitination of lysine 688 in the APP intracellular domain. Our results reveal the mechanistic basis by which ubiquilin-1 regulates APP maturation, with important consequences for the pathogenesis of late-onset AD.

    Original languageEnglish (US)
    Pages (from-to)13416-13421
    Number of pages6
    JournalProceedings of the National Academy of Sciences of the United States of America
    Volume109
    Issue number33
    DOIs
    StatePublished - Aug 14 2012

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    Amyloid beta-Protein Precursor
    Amyloid
    Proteolysis
    Lysine
    Amyloid Precursor Protein Secretases
    Alzheimer Disease
    Peptide Fragments
    Secretory Pathway
    Golgi Apparatus
    Proteasome Endopeptidase Complex
    Single Nucleotide Polymorphism
    Peptides
    Mutation
    Enzymes
    Genes
    Proteins

    Keywords

    • Neurodegeneration
    • Trafficking
    • Ubiquitin-associated domain
    • Ubiquitin-like domain

    ASJC Scopus subject areas

    • General

    Cite this

    Ubiquilin-1 regulates amyloid precursor protein maturation and degradation by stimulating K63-linked polyubiquitination of lysine 688. / Ayadi, Amina El; Stieren, Emily S.; Barral, José M.; Boehning, Darren.

    In: Proceedings of the National Academy of Sciences of the United States of America, Vol. 109, No. 33, 14.08.2012, p. 13416-13421.

    Research output: Contribution to journalArticle

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