| Degradation of the sodium taurocholate cotransporting polypeptide (NTCP) by the ubiquitin-proteasome system. | |
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MedLine Citation:
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PMID: 16218878 Owner: NLM Status: MEDLINE |
Abstract/OtherAbstract:
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The sodium taurocholate cotransporting polypeptide (Ntcp, Slc10a1) is the major uptake system for bile acids into liver cells. This study investigated the degradation of rat Ntcp and human NTCP by the ubiquitin-proteasome system (UPS). In stably transfected HepG2 cells, rat Ntcp was complex-glycosylated and localized at the plasma membrane. Inhibition of proteasomes by MG-132 or lactacystin led to the accumulation of intracellular Ntcp, a process dependent on de novo protein synthesis. Intracellular Ntcp was core-glycosylated, indicating an endoplasmic reticulum (ER) origin. Core-glycosylated Ntcp was found in cytosolic, detergent-insoluble deposits with characteristics of aggresomes: they co-localized with ubiquitin at the microtubule organization center and Ntcp from these deposits was polyubiquitinated. Transient transfections of Ntcp/NTCP induced intracellular deposits that co-localized with ubiquitin, even in the absence of proteasome inhibitors. Similarly, in livers of patients with progressive familial intrahepatic cholestasis, NTCP could be detected co-localized with ubiquitin in hepatocytes. We conclude that maturing Ntcp/NTCP is degraded by the ubiquitin-proteasome system at the level of ER-associated degradation (ERAD). An imbalance in the synthesis and degradation of NTCP at the level of the ER or alterations in the ERAD machinery might be the cause of intracellular NTCP deposits in transient transfections and in cholestatic livers. |
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Authors:
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Thomas Kühlkamp; Verena Keitel; Angelika Helmer; Dieter Häussinger; Ralf Kubitz |
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Publication Detail:
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Type: Journal Article; Research Support, Non-U.S. Gov't |
Journal Detail:
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Title: Biological chemistry Volume: 386 ISSN: 1431-6730 ISO Abbreviation: Biol. Chem. Publication Date: 2005 Oct |
Date Detail:
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Created Date: 2005-10-12 Completed Date: 2005-12-13 Revised Date: 2006-11-15 |
Medline Journal Info:
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Nlm Unique ID: 9700112 Medline TA: Biol Chem Country: Germany |
Other Details:
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Languages: eng Pagination: 1065-74 Citation Subset: IM |
Affiliation:
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Department of Gastroenterology, Hepatology and Infectiology, Heinrich-Heine University, D-40225 Düsseldorf, Germany. |
Export Citation:
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| MeSH Terms | |
Descriptor/Qualifier:
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Animals Cell Membrane / chemistry Cells, Cultured Cholestasis / metabolism Cysteine Proteinase Inhibitors / pharmacology Cytosol / chemistry Endoplasmic Reticulum / metabolism Glycosylation Humans Leupeptins / pharmacology Liver / chemistry, pathology Membrane Transport Proteins / analysis, genetics, metabolism* Organic Anion Transporters, Sodium-Dependent Proteasome Endopeptidase Complex / antagonists & inhibitors, metabolism* Rats Symporters Ubiquitin / analysis, metabolism* |
| Chemical | |
Reg. No./Substance:
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0/Cysteine Proteinase Inhibitors; 0/Leupeptins; 0/Membrane Transport Proteins; 0/Organic Anion Transporters, Sodium-Dependent; 0/Symporters; 0/Ubiquitin; 133407-82-6/benzyloxycarbonylleucyl-leucyl-leucine aldehyde; 145420-23-1/sodium-bile acid cotransporter; EC 3.4.25.1/Proteasome Endopeptidase Complex |
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine
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