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Anthrax toxin triggers endocytosis of its receptor via a lipid raft–mediated clathrin-dependent process

The protective antigen (PA) of the anthrax toxin binds to a cell surface receptor and thereby allows lethal factor (LF) to be taken up and exert its toxic effect in the cytoplasm. Here, we report that clustering of the anthrax toxin receptor (ATR) with heptameric PA or with an antibody sandwich caus...

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Autores principales: Abrami, Laurence, Liu, Shihui, Cosson, Pierre, Leppla, Stephen H., van der Goot, F. Gisou
Formato: Texto
Lenguaje:English
Publicado: The Rockefeller University Press 2003
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2172673/
https://www.ncbi.nlm.nih.gov/pubmed/12551953
http://dx.doi.org/10.1083/jcb.200211018
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author Abrami, Laurence
Liu, Shihui
Cosson, Pierre
Leppla, Stephen H.
van der Goot, F. Gisou
author_facet Abrami, Laurence
Liu, Shihui
Cosson, Pierre
Leppla, Stephen H.
van der Goot, F. Gisou
author_sort Abrami, Laurence
collection PubMed
description The protective antigen (PA) of the anthrax toxin binds to a cell surface receptor and thereby allows lethal factor (LF) to be taken up and exert its toxic effect in the cytoplasm. Here, we report that clustering of the anthrax toxin receptor (ATR) with heptameric PA or with an antibody sandwich causes its association to specialized cholesterol and glycosphingolipid-rich microdomains of the plasma membrane (lipid rafts). We find that although endocytosis of ATR is slow, clustering it into rafts either via PA heptamerization or using an antibody sandwich is necessary and sufficient to trigger efficient internalization and allow delivery of LF to the cytoplasm. Importantly, altering raft integrity using drugs prevented LF delivery and cleavage of cytosolic MAPK kinases, suggesting that lipid rafts could be therapeutic targets for drugs against anthrax. Moreover, we show that internalization of PA is dynamin and Eps15 dependent, indicating that the clathrin-dependent pathway is the major route of anthrax toxin entry into the cell. The present work illustrates that although the physiological role of the ATR is unknown, its trafficking properties, i.e., slow endocytosis as a monomer and rapid clathrin-mediated uptake on clustering, make it an ideal anthrax toxin receptor.
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spelling pubmed-21726732008-05-01 Anthrax toxin triggers endocytosis of its receptor via a lipid raft–mediated clathrin-dependent process Abrami, Laurence Liu, Shihui Cosson, Pierre Leppla, Stephen H. van der Goot, F. Gisou J Cell Biol Report The protective antigen (PA) of the anthrax toxin binds to a cell surface receptor and thereby allows lethal factor (LF) to be taken up and exert its toxic effect in the cytoplasm. Here, we report that clustering of the anthrax toxin receptor (ATR) with heptameric PA or with an antibody sandwich causes its association to specialized cholesterol and glycosphingolipid-rich microdomains of the plasma membrane (lipid rafts). We find that although endocytosis of ATR is slow, clustering it into rafts either via PA heptamerization or using an antibody sandwich is necessary and sufficient to trigger efficient internalization and allow delivery of LF to the cytoplasm. Importantly, altering raft integrity using drugs prevented LF delivery and cleavage of cytosolic MAPK kinases, suggesting that lipid rafts could be therapeutic targets for drugs against anthrax. Moreover, we show that internalization of PA is dynamin and Eps15 dependent, indicating that the clathrin-dependent pathway is the major route of anthrax toxin entry into the cell. The present work illustrates that although the physiological role of the ATR is unknown, its trafficking properties, i.e., slow endocytosis as a monomer and rapid clathrin-mediated uptake on clustering, make it an ideal anthrax toxin receptor. The Rockefeller University Press 2003-02-03 /pmc/articles/PMC2172673/ /pubmed/12551953 http://dx.doi.org/10.1083/jcb.200211018 Text en Copyright © 2003, The Rockefeller University Press This article is distributed under the terms of an Attribution–Noncommercial–Share Alike–No Mirror Sites license for the first six months after the publication date (see http://www.rupress.org/terms). After six months it is available under a Creative Commons License (Attribution–Noncommercial–Share Alike 4.0 Unported license, as described at http://creativecommons.org/licenses/by-nc-sa/4.0/).
spellingShingle Report
Abrami, Laurence
Liu, Shihui
Cosson, Pierre
Leppla, Stephen H.
van der Goot, F. Gisou
Anthrax toxin triggers endocytosis of its receptor via a lipid raft–mediated clathrin-dependent process
title Anthrax toxin triggers endocytosis of its receptor via a lipid raft–mediated clathrin-dependent process
title_full Anthrax toxin triggers endocytosis of its receptor via a lipid raft–mediated clathrin-dependent process
title_fullStr Anthrax toxin triggers endocytosis of its receptor via a lipid raft–mediated clathrin-dependent process
title_full_unstemmed Anthrax toxin triggers endocytosis of its receptor via a lipid raft–mediated clathrin-dependent process
title_short Anthrax toxin triggers endocytosis of its receptor via a lipid raft–mediated clathrin-dependent process
title_sort anthrax toxin triggers endocytosis of its receptor via a lipid raft–mediated clathrin-dependent process
topic Report
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2172673/
https://www.ncbi.nlm.nih.gov/pubmed/12551953
http://dx.doi.org/10.1083/jcb.200211018
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