| Glucosylceramide synthesis inhibition affects cell cycle progression, membrane trafficking, and stage differentiation in Giardia lamblia. | |
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MedLine Citation:
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PMID: 20335568 Owner: NLM Status: MEDLINE |
Abstract/OtherAbstract:
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Synthesis of glucosylceramide via glucosylceramide synthase (GCS) is a crucial event in higher eukaryotes, both for the production of complex glycosphingolipids and for regulating cellular levels of ceramide, a potent antiproliferative second messenger. In this study, we explored the dependence of the early branching eukaryote Giardia lamblia on GCS activity. Biochemical analyses revealed that the parasite has a GCS located in endoplasmic reticulum (ER) membranes that is active in proliferating and encysting trophozoites. Pharmacological inhibition of GCS induced aberrant cell division, characterized by arrest of cytokinesis, incomplete cleavage furrow formation, and consequent block of replication. Importantly, we showed that increased ceramide levels were responsible for the cytokinesis arrest. In addition, GCS inhibition resulted in prominent ultrastructural abnormalities, including accumulation of cytosolic vesicles, enlarged lysosomes, and clathrin disorganization. Moreover, anterograde trafficking of the encystations-specific protein CWP1 was severely compromised and resulted in inhibition of stage differentiation. Our results reveal novel aspects of lipid metabolism in G. lamblia and specifically highlight the vital role of GCS in regulating cell cycle progression, membrane trafficking events, and stage differentiation in this parasite. In addition, we identified ceramide as a potent bioactive molecule, underscoring the universal conservation of ceramide signaling in eukaryotes. |
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Authors:
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Sasa Stefanić; Cornelia Spycher; Laura Morf; Gemma Fabriàs; Josefina Casas; Elisabeth Schraner; Peter Wild; Adrian B Hehl; Sabrina Sonda |
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Publication Detail:
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Type: Journal Article; Research Support, Non-U.S. Gov't Date: 2010-03-24 |
Journal Detail:
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Title: Journal of lipid research Volume: 51 ISSN: 0022-2275 ISO Abbreviation: J. Lipid Res. Publication Date: 2010 Sep |
Date Detail:
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Created Date: 2010-08-12 Completed Date: 2011-02-14 Revised Date: 2011-09-13 |
Medline Journal Info:
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Nlm Unique ID: 0376606 Medline TA: J Lipid Res Country: United States |
Other Details:
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Languages: eng Pagination: 2527-45 Citation Subset: IM |
Affiliation:
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Institute of Parasitology, University of Zurich, Zurich, Switzerland. |
Export Citation:
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| MeSH Terms | |
Descriptor/Qualifier:
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Amino Acid Sequence Animals Biological Transport / physiology Cell Cycle / physiology* Cell Differentiation / physiology* Cell Membrane / metabolism* Ceramides / metabolism, pharmacology Clathrin / metabolism Endoplasmic Reticulum / enzymology Giardia lamblia / drug effects, physiology*, ultrastructure Glucosylceramides / biosynthesis* Glucosyltransferases / metabolism Humans Lipid Metabolism Meperidine / analogs & derivatives, pharmacology Molecular Sequence Data Sequence Alignment Sphingolipids / metabolism Trophozoites / metabolism |
| Chemical | |
Reg. No./Substance:
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0/Ceramides; 0/Clathrin; 0/Glucosylceramides; 0/Sphingolipids; 13147-09-6/4-propionyloxy-4-phenyl-N-methylpiperidine; 57-42-1/Meperidine; EC 2.4.1.-/Glucosyltransferases; EC 2.4.1.80/ceramide glucosyltransferase |
| Comments/Corrections | |
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