Ubiquilin-1 Modulates γ-Secretase-Mediated ε-Site Cleavage in Neuronal Cells
| Autor: | Lars Bertram, Kaisa M.A. Kurkinen, Rudolph E. Tanzi, Annakaisa Haapasalo, Jayashree Viswanathan, Petra Mäkinen, Teemu Natunen, Hilkka Soininen, Mikko Hiltunen |
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| Rok vydání: | 2013 |
| Předmět: |
biology
Chemistry Phosphatase Receptor-Like Protein Tyrosine Phosphatases Class 2 Autophagy-Related Proteins Cell Cycle Proteins Biochemistry Peptide Fragments Presenilin Cell biology Amyloid beta-Protein Precursor Alpha secretase Cell Line Tumor mental disorders biology.protein Amyloid precursor protein Humans Secretion Amyloid Precursor Protein Secretases APH-1 Carrier Proteins Amyloid precursor protein secretase Gamma secretase Adaptor Proteins Signal Transducing |
| Zdroj: | Biochemistry. 52:3899-3912 |
| ISSN: | 1520-4995 0006-2960 |
| Popis: | Ubiquilin-1 is an Alzheimer's disease-associated protein, which is known to modulate amyloid precursor protein (APP) processing, amyloid-β (Aβ) secretion, and presenilin-1 (PS1) accumulation. Here, we aim to elucidate the molecular mechanisms by which full-length transcript variant 1 of ubiquilin-1 (TV1) affects APP processing and γ-secretase function in human neuroblastoma cells stably overexpressing APP (SH-SY5Y-APP751). We found that TV1 overexpression significantly increased the level of APP intracellular domain (AICD) generation. However, there was no increase in the levels of secreted Aβ40, Aβ42, or total Aβ, suggesting that ubiquilin-1 in particular enhances γ-secretase-mediated ε-site cleavage. This is supported by the finding that TV1 also significantly increased the level of intracellular domain generation of another γ-secretase substrate, leukocyte common antigen-related (LAR) phosphatase. However, in these cells, the increase in AICD levels was abolished, suggesting a preference of the γ-secretase for LAR over APP. TV2, another ubiquilin-1 variant that lacks the protein fragment encoded by exon 8, did not increase the level of AICD generation like TV1 did. The subcellular and plasma membrane localization of APP or γ-secretase complex components PS1 and nicastrin was not altered in TV1-overexpressing cells. Moreover, the effects of TV1 were not mediated by altered expression or APP binding of FE65, an adaptor protein thought to regulate AICD generation and stability. These data suggest that ubiquilin-1 modulates γ-secretase-mediated ε-site cleavage and thus may play a role in regulating γ-secretase cleavage of various substrates. |
| Databáze: | OpenAIRE |
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