ArticleThe Journal of biological chemistry2012
BACE1 protein endocytosis and trafficking are differentially regulated by ubiquitination at lysine 501 and the Di-leucine motif in the carboxyl terminus.
Article in The Journal of biological chemistry, 2012. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 31 papers.
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Who cites it
31 citing papers in PubMed, 53 citations in OpenAlex.
- DUBs in Alzheimer's disease: mechanisms and therapeutic implications.Cell death discovery · 2024Review
- The Involvement of Post-Translational Modifications in Regulating the Development and Progression of Alzheimer's Disease.Molecular neurobiology · 2023Review
- Fangchinoline alleviates cognitive impairments through enhancing autophagy and mitigating oxidative stress in Alzheimer's disease models.Frontiers in cell and developmental biology · 2023Article
- In vivo delivery of CRISPR-Cas9 genome editing components for therapeutic applications.Biomaterials · 2022Review
- Impaired autophagy in amyloid-beta pathology: A traditional review of recent Alzheimer's research.Journal of biomedical research · 2022Article
- USP25 inhibition ameliorates Alzheimer's pathology through the regulation of APP processing and Aβ generation.The Journal of clinical investigation · 2022Article
- Post-Translational Modifications of BACE1 in Alzheimer's Disease.Current neuropharmacology · 2022Article
- Deubiquitinating enzymes (DUBs): decipher underlying basis of neurodegenerative diseases.Molecular psychiatry · 2022Review
- The aminosterol Claramine inhibits β-secretase 1-mediated insulin receptor cleavage.The Journal of biological chemistry · 2021Article
- The β-Secretase BACE1 in Alzheimer's Disease.Biological psychiatry · 2021Review
- AP-2 reduces amyloidogenesis by promoting BACE1 trafficking and degradation in neurons.EMBO reports · 2020Article
- Paricalcitol accelerates BACE1 lysosomal degradation and inhibits calpain-1 dependent neuronal loss in APP/PS1 transgenic mice.EBioMedicine · 2019Article
- A GFP-tagged version of the pseudorabies virus protein UL56 localizes to the Golgi and trans-Golgi network through a predicted C-terminal leucine-rich helix in transfected cells.Virology journal · 2019Article
- Article
- In vivo neuronal gene editing via CRISPR-Cas9 amphiphilic nanocomplexes alleviates deficits in mouse models of Alzheimer's disease.Nature neuroscience · 2019Article
- BACE1 SUMOylation increases its stability and escalates the protease activity in Alzheimer's disease.Proceedings of the National Academy of Sciences of the United States of America · 2018Article
- BACE1 elevation engendered by GGA3 deletion increases β-amyloid pathology in association with APP elevation and decreased CHL1 processing in 5XFAD mice.Molecular neurodegeneration · 2018Article
- Disruption of amyloid precursor protein ubiquitination selectively increases amyloid β (Aβ) 40 levels via presenilin 2-mediated cleavage.The Journal of biological chemistry · 2017Article
- BACE1 Function and Inhibition: Implications of Intervention in the Amyloid Pathway of Alzheimer's Disease Pathology.Molecules (Basel, Switzerland) · 2017Review
- Prediction of intracellular exposure bridges the gap between target- and cell-based drug discovery.Proceedings of the National Academy of Sciences of the United States of America · 2017Article
Corrections and comments
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Authors and funding
4 authors at 1 institution in 1 country.
Funding
Abstract
β-Site amyloid precursor protein-cleaving enzyme (BACE1) is a membrane-tethered member of the aspartyl proteases that has been identified as β-secretase. BACE1 is targeted through the secretory pathway to the plasma membrane and then is internalized to endosomes. Sorting of membrane proteins to the endosomes and lysosomes is regulated by the interaction of signals present in their carboxyl-terminal fragment with specific trafficking molecules. The BACE1 carboxyl-terminal fragment contains a di-leucine sorting signal ((495)DDISLL(500)) and a ubiquitination site at Lys-501. Here, we report that lack of ubiquitination at Lys-501 (BACE1K501R) does not affect the rate of endocytosis but produces BACE1 stabilization and accumulation of BACE1 in early and late endosomes/lysosomes as well as at the cell membrane. In contrast, the disruption of the di-leucine motif (BACE1LLAA) greatly impairs BACE1 endocytosis and produces a delayed retrograde transport of BACE1 to the trans-Golgi network (TGN) and a delayed delivery of BACE1 to the lysosomes, thus decreasing its degradation. Moreover, the combination of the lack of ubiquitination at Lys-501 and the disruption of the di-leucine motif (BACE1LLAA/KR) produces additive effects on BACE1 stabilization and defective internalization. Finally, BACE1LLAA/KR accumulates in the TGN, while its levels are decreased in EEA1-positive compartments indicating that both ubiquitination at Lys-501 and the di-leucine motif are necessary for the trafficking of BACE1 from the TGN to early endosomes. Our studies have elucidated a differential role for the di-leucine motif and ubiquitination at Lys-501 in BACE1 endocytosis, trafficking, and degradation and suggest the involvement of multiple adaptor molecules.
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Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.