ArticleThe Journal of biological chemistry2006
Cholesterol accumulation sequesters Rab9 and disrupts late endosome function in NPC1-deficient cells.
Article in The Journal of biological chemistry, 2006. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 60 papers.
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Who cites it
60 citing papers in PubMed, 112 citations in OpenAlex.
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- The Role of Rab GTPases in the development of genetic and malignant diseases.Molecular and cellular biochemistry · 2024Review
- Linking Late Endosomal Cholesterol with Cancer Progression and Anticancer Drug Resistance.International journal of molecular sciences · 2022Review
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- Salmonella Typhimurium manipulates macrophage cholesterol homeostasis through the SseJ-mediated suppression of the host cholesterol transport protein ABCA1.Cellular microbiology · 2021Article
- Lipid-mediated motor-adaptor sequestration impairs axonal lysosome delivery leading to autophagic stress and dystrophy in Niemann-Pick type C.Developmental cell · 2021Article
- Possible therapeutic targets for SARS-CoV-2 infection and COVID-19.Journal of allergy and infectious diseases · 2021Article
- Adenovirus Reveals New Pathway for Cholesterol Egress from the Endolysosomal System.International journal of molecular sciences · 2020Review
- Role of Endolysosomes in Severe Acute Respiratory Syndrome Coronavirus-2 Infection and Coronavirus Disease 2019 Pathogenesis: Implications for Potential Treatments.Frontiers in pharmacology · 2020Article
- Lipid⁻Protein Interactions in Niemann⁻Pick Type C Disease: Insights from Molecular Modeling.International journal of molecular sciences · 2019Article
- Annexins-Coordinators of Cholesterol Homeostasis in Endocytic Pathways.International journal of molecular sciences · 2018Review
- Consequences of Rab GTPase dysfunction in genetic or acquired human diseases.Small GTPases · 2018Review
- LAMTOR/Ragulator is a negative regulator of Arl8b- and BORC-dependent late endosomal positioning.The Journal of cell biology · 2017Article
- Emerging Roles for the Lysosome in Lipid Metabolism.Trends in cell biology · 2017Review
- Insulin-Like Growth Factor-II/Cation-Independent Mannose 6-Phosphate Receptor in Neurodegenerative Diseases.Molecular neurobiology · 2017Review
- Clustering of Rab11 vesicles in influenza A virus infected cells creates hotspots containing the 8 viral ribonucleoproteins.Small GTPases · 2017Review
- Mechanisms and functions of lysosome positioning.Journal of cell science · 2016Review
- Rab13 Traffics on Vesicles Independent of Prenylation.The Journal of biological chemistry · 2016Article
- Recycling Endosomes and Viral Infection.Viruses · 2016Review
Corrections and comments
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Authors and funding
2 authors at 1 institution in 1 country.
Funding
Abstract
Niemann-Pick type C disease is an autosomal recessive disorder that leads to massive accumulation of cholesterol and glycosphingolipids in late endosomes and lysosomes. To understand how cholesterol accumulation influences late endosome function, we investigated the effect of elevated cholesterol on Rab9-dependent export of mannose 6-phosphate receptors from this compartment. Endogenous Rab9 levels were elevated 1.8-fold in Niemann-Pick type C cells relative to wild type cells, and its half-life increased 1.6-fold, suggesting that Rab9 accumulation is caused by impaired protein turnover. Reduced Rab9 degradation was accompanied by stabilization on endosome membranes, as shown by a reduction in the capacity of Rab9 for guanine nucleotide dissociation inhibitor-mediated extraction from Niemann-Pick type C membranes. Cholesterol appeared to stabilize Rab9 directly, as liposomes loaded with prenylated Rab9 showed decreased extractability with increasing cholesterol content. Rab9 is likely sequestered in an inactive form on Niemann-Pick type C membranes, as cation-dependent mannose 6-phosphate receptors were missorted to the lysosome for degradation, a process that was reversed by overexpression of GFP-tagged Rab9. In addition to using primary fibroblasts isolated from Niemann-Pick type C patients, RNA interference was utilized to recapitulate the disease phenotype in cultured cells, greatly facilitating the analysis of cholesterol accumulation and late endosome function. We conclude that cholesterol contributes directly to the sequestration of Rab9 on Niemann-Pick type C cell membranes, which in turn, disrupts mannose 6-phosphate receptor trafficking.
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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.