ArticleThe Journal of biological chemistry2016
The Endosome-associated Deubiquitinating Enzyme USP8 Regulates BACE1 Enzyme Ubiquitination and Degradation.
Article in The Journal of biological chemistry, 2016. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 46 papers, 1 of them a synthesis that pooled it.
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Who cites it
46 citing papers in PubMed, 1 synthesis or guideline pooled it, 70 citations in OpenAlex.
- The Emerging Roles of E3 Ligases and DUBs in Neurodegenerative Diseases.Molecular neurobiology · 2023Pooled it
- UPS-mediated P-glycoprotein regulation in Alzheimer's disease: pharmacological implications for the amyloid pathology.Molecular biology reports · 2026Review
- Mitofusin-2 in ventral striatal D1 neurons regulates effort-based motivation through sex-specific mitochondrial-synaptic reprogramming.Proceedings of the National Academy of Sciences of the United States of America · 2026Article
- Neuroinflammation-induced downregulation of RAB7 in murine astrocytes disrupts endo-lysosomal homeostasis and induces astrogliosis.Cell communication and signaling : CCS · 2026Article
- Molecular Mechanisms of the Ubiquitin-Specific Proteases (USPs) Family in Biliary Tract Cancer and Targeted Intervention Strategies.Biomedicines · 2025Review
- Roles of Ubiquitin Ligases and Deubiquitylases in Alzheimer's Disease.Molecular neurobiology · 2025Review
- The role of exosomal non-coding RNAs in the breast cancer tumor microenvironment.Functional & integrative genomics · 2025Review
- Molecular Symphony of Mitophagy: Ubiquitin-Specific Protease-30 as a Maestro for Precision Management of Neurodegenerative Diseases.CNS neuroscience & therapeutics · 2025Review
- Charting the shared genetic architecture of Alzheimer's disease, cognition, and educational attainment, and associations with brain development.Neurobiology of disease · 2024Article
- DUBs in Alzheimer's disease: mechanisms and therapeutic implications.Cell death discovery · 2024Review
- The role of ubiquitination in health and disease.MedComm · 2024Review
- Genetic architecture of hippocampus subfields volumes in Alzheimer's disease.CNS neuroscience & therapeutics · 2024Article
- Exosome regulation of immune response mechanism: Pros and cons in immunotherapy.Bioactive materials · 2024Article
- The Involvement of Post-Translational Modifications in Regulating the Development and Progression of Alzheimer's Disease.Molecular neurobiology · 2023Review
- Recent advances in the roles of exosomal microRNAs (exomiRs) in hematologic neoplasms: pathogenesis, diagnosis, and treatment.Cell communication and signaling : CCS · 2023Review
- Article
- The Role of Exosomes in Epithelial-to-Mesenchymal Transition and Cell Functional Properties in Head and Neck Cancer.Cancers · 2023Review
- Fangchinoline alleviates cognitive impairments through enhancing autophagy and mitigating oxidative stress in Alzheimer's disease models.Frontiers in cell and developmental biology · 2023Article
- Impact of Exosomes Released by Different Corneal Cell Types on the Wound Healing Properties of Human Corneal Epithelial Cells.International journal of molecular sciences · 2022Article
- Mesenchymal stem cell-derived exosomes in cancer therapy resistance: recent advances and therapeutic potential.Molecular cancer · 2022Review
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Authors and funding
2 authors at 1 institution in 1 country.
Funding
Abstract
The β-site amyloid precursor protein-cleaving enzyme (BACE1) is the rate-limiting enzyme in the production of amyloid-β, the toxic peptide that accumulates in the brain of subjects affected by Alzheimer disease. Our previous studies have shown that BACE1 is degraded via the lysosomal pathway and that that depletion of the trafficking molecule Golgi-localized γ-ear-containing ARF-binding protein 3 (GGA3) results in increased BACE1 levels and activity because of impaired lysosomal degradation. We also determined that GGA3 regulation of BACE1 levels requires its ability to bind ubiquitin. Accordingly, we reported that BACE1 is ubiquitinated at lysine 501 and that lack of ubiquitination at lysine 501 produces BACE1 stabilization. Ubiquitin conjugation is a reversible process mediated by deubiquitinating enzymes. The ubiquitin-specific peptidase 8 (USP8), an endosome-associated deubiquitinating enzyme, regulates the ubiquitination, trafficking, and lysosomal degradation of several plasma membrane proteins. Here, we report that RNAi-mediated depletion of USP8 reduced levels of both ectopically expressed and endogenous BACE1 in H4 human neuroglioma cells. Moreover, USP8 depletion increased BACE1 ubiquitination, promoted BACE1 accumulation in the early endosomes and late endosomes/lysosomes, and decreased levels of BACE1 in the recycling endosomes. We also found that decreased BACE1 protein levels were accompanied by a decrease in BACE1-mediated amyloid precursor protein cleavage and amyloid-β levels. Our findings demonstrate that USP8 plays a key role in the trafficking and degradation of BACE1 by deubiquitinating lysine 501. These studies suggest that therapies able to accelerate BACE1 degradation (e.g. by increasing BACE1 ubiquitination) may represent a potential treatment for Alzheimer disease.
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Registered trials
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.