Utilize este identificador para referenciar este registo:
https://hdl.handle.net/1822/62019
Título: | Disruption of amyloid precursor protein ubiquitination selectively increases amyloid β (Aβ) 40 levels via presenilin 2-mediated cleavage |
Autor(es): | Williamson, Rebecca L. Laulagnier, Karine Miranda, André M. Fernandez, Marty A. Wolfe, Michael S. Sadoul, Rémy Di Paolo, Gilbert |
Palavras-chave: | Amyloid beta-Peptides Amyloid beta-Protein Precursor Arginine Cell Line Endosomes Humans Lysine Mutation Peptide Fragments Presenilin-2 Proteolysis Ubiquitination Alzheimer disease amyloid precursor protein (APP) amyloid- (A) endosome intracellular processing intracellular trafficking lysosome presenilin |
Data: | 2017 |
Editora: | American Society for Biochemistry and Molecular Biology |
Revista: | Journal of Biological Chemistry |
Resumo(s): | Amyloid plaques, a neuropathological hallmark of Alzheimer's disease, are largely composed of amyloid β (Aβ) peptide, derived from cleavage of amyloid precursor protein (APP) by β- and γ-secretases. The endosome is increasingly recognized as an important crossroad for APP and these secretases, with major implications for APP processing and amyloidogenesis. Among various post-translational modifications affecting APP accumulation, ubiquitination of cytodomain lysines may represent a key signal controlling APP endosomal sorting. Here, we show that substitution of APP C-terminal lysines with arginine disrupts APP ubiquitination and that an increase in the number of substituted lysines tends to increase APP metabolism. An APP mutant lacking all C-terminal lysines underwent the most pronounced increase in processing, leading to accumulation of both secreted and intracellular Aβ40. Artificial APP ubiquitination with rapalog-mediated proximity inducers reduced Aβ40 generation. A lack of APP C-terminal lysines caused APP redistribution from endosomal intraluminal vesicles (ILVs) to the endosomal limiting membrane, with a subsequent decrease in APP C-terminal fragment (CTF) content in secreted exosomes, but had minimal effects on APP lysosomal degradation. Both the increases in secreted and intracellular Aβ40 were abolished by depletion of presenilin 2 (PSEN2), recently shown to be enriched on the endosomal limiting membrane compared with PSEN1. Our findings demonstrate that ubiquitin can act as a signal at five cytodomain-located lysines for endosomal sorting of APP. They further suggest that disruption of APP endosomal sorting reduces its sequestration in ILVs and results in PSEN2-mediated processing of a larger pool of APP-CTF on the endosomal membrane. |
Tipo: | Artigo |
URI: | https://hdl.handle.net/1822/62019 |
DOI: | 10.1074/jbc.M117.818138 |
ISSN: | 0021-9258 |
e-ISSN: | 1083-351X |
Arbitragem científica: | yes |
Acesso: | Acesso aberto |
Aparece nas coleções: | ICVS - Artigos em revistas internacionais / Papers in international journals |
Ficheiros deste registo:
Ficheiro | Descrição | Tamanho | Formato | |
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Williamson-2017-Disruption-of-amyloid-precursor-pro.pdf | 3,81 MB | Adobe PDF | Ver/Abrir |