title: Ubiquilin-1 regulates amyloid precursor protein maturation and degradation by stimulating K63-linked polyubiquitination of lysine 688.
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.
authors: Department of Neuroscience and Cell Biology, University of Texas Medical Branch, Galveston, TX 77555, USA.
authors: Amina
authors: A
authors: El Ayadi
authors: Emily S
authors: ES
authors: Stieren
authors: José M
authors: JM
authors: Barral
authors: Darren
authors: D
authors: Boehning
mesh_terms: D033942:Adaptor Proteins, Vesicular Transport / Q000378:metabolism*; D053829:Amyloid Precursor Protein Secretases / Q000378:metabolism; D016564:Amyloid beta-Protein Precursor / Q000378:metabolism*; D000818:Animals; D006056:Golgi Apparatus / Q000378:metabolism; D049452:Green Fluorescent Proteins / Q000378:metabolism; D008239:Lysine / Q000378:metabolism*; D008247:Lysosomes / Q000378:metabolism; D018832:Molecular Chaperones / Q000378:metabolism*; D016716:PC12 Cells; D025821:Polyubiquitin / Q000378:metabolism*; D011499:Protein Processing, Post-Translational; D021381:Protein Transport; D059748:Proteolysis; D051381:Rats; D011993:Recombinant Fusion Proteins / Q000378:metabolism; D055571:Secretory Pathway; D054875:Ubiquitination
chemical_list: D033942:Adaptor Proteins, Vesicular Transport; D016564:Amyloid beta-Protein Precursor; D018832:Molecular Chaperones; D011993:Recombinant Fusion Proteins; C575873:Ubqln1 protein, rat; D025821:Polyubiquitin; D049452:Green Fluorescent Proteins; D053829:Amyloid Precursor Protein Secretases; D008239:Lysine