Smith, Daniel C. , Sillence, Daniel J., Falguières, Thomas, Jarvis, Rosemary M., Johannes, Ludger, Lord, Mike (J. Mike), Platt, Frances M. and Roberts, Lynne M. . (2006) The association of shiga-like toxin with detergent-resistant membranes is modulated by glucosylceramide and is an essential requirement in the endoplasmic reticulum for a cytotoxic effect. Molecular Biology of the Cell, Vol.17 (No.3). pp. 1375-1387. ISSN 1059-1524

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Abstract

Receptor-mediated internalization to the endoplasmic reticulum (ER) and subsequent retro-translocation to the cytosol are essential sequential processes required for the productive intoxication of susceptible mammalian cells by Shiga-like toxin-1 (SLTx). Recently, it has been proposed that the observed association of certain ER-directed toxins and viruses with detergent-resistant membranes (DRM) may provide a general mechanism for their retrograde transport to endoplasmic reticulum (ER). Here, we show that DRM recruitment of SLTx bound to its globotriosylceramide (Gb3) receptor is mediated by the availability of other glycosphingolipids. Reduction in glucosylceramide (GlcCer) levels led to complete protection against SLTx and a reduced cell surface association of bound toxin with DRM. This reduction still allowed efficient binding and transport of the toxin to the ER. However, toxin sequestration within DRM of the ER was abolished under reduced GlcCer conditions, suggesting that an association of toxin with lipid microdomains or rafts in the ER (where these are defined by detergent insolubility) is essential for a later step leading to or involving retro-translocation of SLTx across the ER membrane. In support of this, we show that a number of ER residents, proteins intimately involved in the process of ER dislocation of misfolded proteins, are present in DRM.

Item Type:	Journal Article
Subjects:	Q Science > QR Microbiology
Divisions:	Faculty of Science > Life Sciences (2010- ) > Biological Sciences ( -2010)
Library of Congress Subject Headings (LCSH):	Verocytotoxins, Endoplasmic reticulum, Cell receptors, Glycosphingolipids, Ceramides, Cytology -- Research
Journal or Publication Title:	Molecular Biology of the Cell
Publisher:	American Society for Cell Biology
ISSN:	1059-1524
Date:	March 2006
Volume:	Vol.17
Number:	No.3
Page Range:	pp. 1375-1387
Identification Number:	10.1091/mbc.E05-11-1035
Status:	Peer Reviewed
Access rights to Published version:	Open Access
Funder:	Biotechnology and Biological Sciences Research Council (Great Britain) (BBSRC), Wellcome Trust (London, England), Ara Parseghian Medical Research Foundation (APMRF), Action Medical Research (AMR), Ligue nationale contre le cancer (France) (LNCC), Fondation de France, Fondation pour la recherche médicale (FRM)
Grant number:	063058/Z/00/Z (Wellcome), 5177 (LNCC), 3105 (LNCC), 5233(FF)
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URI:	http://wrap.warwick.ac.uk/id/eprint/940

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