24
views
0
recommends
+1 Recommend
0 collections
    0
    shares
      • Record: found
      • Abstract: found
      • Article: not found

      Late Endosomal Cholesterol Accumulation Leads to Impaired Intra-Endosomal Trafficking

      research-article

      Read this article at

      ScienceOpenPublisherPMC
      Bookmark
          There is no author summary for this article yet. Authors can add summaries to their articles on ScienceOpen to make them more accessible to a non-specialist audience.

          Abstract

          Background

          Pathological accumulation of cholesterol in late endosomes is observed in lysosomal storage diseases such as Niemann-Pick type C. We here analyzed the effects of cholesterol accumulation in NPC cells, or as phenocopied by the drug U18666A, on late endosomes membrane organization and dynamics.

          Methodology/Principal Findings

          Cholesterol accumulation did not lead to an increase in the raft to non-raft membrane ratio as anticipated. Strikingly, we observed a 2–3 fold increase in the size of the compartment. Most importantly, properties and dynamics of late endosomal intralumenal vesicles were altered as revealed by reduced late endosomal vacuolation induced by the mutant pore-forming toxin ASSP, reduced intoxication by the anthrax lethal toxin and inhibition of infection by the Vesicular Stomatitis Virus.

          Conclusions/Significance

          These results suggest that back fusion of intralumenal vesicles with the limiting membrane of late endosomes is dramatically perturbed upon cholesterol accumulation.

          Related collections

          Most cited references42

          • Record: found
          • Abstract: found
          • Article: not found

          Role of cholesterol and lipid organization in disease.

          Membrane lipids are essential for biological functions ranging from membrane trafficking to signal transduction. The composition of lipid membranes influences their organization and properties, so it is not surprising that disorders in lipid metabolism and transport have a role in human disease. Significant recent progress has enhanced our understanding of the molecular and cellular basis of lipid-associated disorders such as Tangier disease, Niemann-Pick disease type C and atherosclerosis. These insights have also led to improved understanding of normal physiology.
            Bookmark
            • Record: found
            • Abstract: found
            • Article: not found

            Cell biology of antigen processing in vitro and in vivo.

            The conversion of exogenous and endogenous proteins into immunogenic peptides recognized by T lymphocytes involves a series of proteolytic and other enzymatic events culminating in the formation of peptides bound to MHC class I or class II molecules. Although the biochemistry of these events has been studied in detail, only in the past few years has similar information begun to emerge describing the cellular context in which these events take place. This review thus concentrates on the properties of antigen-presenting cells, especially those aspects of their overall organization, regulation, and intracellular transport that both facilitate and modulate the processing of protein antigens. Emphasis is placed on dendritic cells and the specializations that help account for their marked efficiency at antigen processing and presentation both in vitro and, importantly, in vivo. How dendritic cells handle antigens is likely to be as important a determinant of immunogenicity and tolerance as is the nature of the antigens themselves.
              Bookmark
              • Record: found
              • Abstract: found
              • Article: not found

              A lipid associated with the antiphospholipid syndrome regulates endosome structure and function.

              Little is known about the structure and function of membrane domains in the vacuolar apparatus of animal cells. A unique feature of late endosomes, which are part of the pathway that leads to lysosomes, is that they contain a complex system of poorly characterized internal membranes in their lumen. These endosomes are therefore known as multivesicular or multilamellar organelles. Some proteins distribute preferentially within these internal membranes, whereas others are exclusively localized to the organelle's limiting membrane. The composition and function of this membrane system are poorly understood. Here we show that these internal membranes contain large amounts of a unique lipid, and thus form specialized domains within endosomes. These specialized domains are involved in sorting the multifunctional receptor for insulin-like growth factor 2 and ligands bearing mannose-6-phosphate, in particular lysosomal enzymes. We also show that this unique lipid is a specific antigen for human antibodies associated with the antiphospholipid syndrome. These antibodies may act intracellularly by altering the protein-sorting functions of endosomes.
                Bookmark

                Author and article information

                Contributors
                Role: Academic Editor
                Journal
                PLoS ONE
                plos
                PLoS ONE
                Public Library of Science (San Francisco, USA )
                1932-6203
                2007
                5 September 2007
                : 2
                : 9
                : e851
                Affiliations
                [1 ]Department of Microbiology and Molecular Medicine, University of Geneva, Geneva, Switzerland
                [2 ]Department of Biochemistry, University of Geneva, Geneva, Switzerland
                [3 ]Institute for Molecular Bioscience, Centre for Microscopy and Microanalysis, School of Biomedical Sciences, The University of Queensland, Brisbane, Australia
                [4 ]Ecole Polytechnique Fédérale de Lausanne, Lausanne, Switzerland
                Duke University Medical Center, United States of America
                Author notes
                * To whom correspondence should be addressed. E-mail: gisou.vandergoot@ 123456epfl.ch

                Conceived and designed the experiments: JG RP Fv KS IL PL MF IL. Performed the experiments: RP KS CF IL PL MF IL. Analyzed the data: JG RP Fv KS IL PL MF IL. Contributed reagents/materials/analysis tools: Fv. Wrote the paper: JG Fv KS.

                Article
                07-PONE-RA-01622R1
                10.1371/journal.pone.0000851
                1952175
                17786222
                4fbd5747-1f41-419a-b3b0-c3bd48231452
                Sobo et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
                History
                : 28 June 2007
                : 15 August 2007
                Page count
                Pages: 11
                Categories
                Research Article
                Cell Biology/Membranes and Sorting
                Microbiology/Cellular Microbiology and Pathogenesis

                Uncategorized
                Uncategorized

                Comments

                Comment on this article