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Published online 27 January 2003. doi:10.1083/jcb.200211018
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© The Rockefeller University Press, 0021-9525/2003/2/321 $5.00
The Journal of Cell Biology, Volume 160, Number 3, 321-328

Report

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

Laurence Abrami1, Shihui Liu3, Pierre Cosson2, Stephen H. Leppla3 and F. Gisou van der Goot1

1 Department of Genetics and Microbiology, University of Geneva, 1211 Geneva 4, Switzerland
2 Department of Morphology, University of Geneva, 1211 Geneva 4, Switzerland
3 Microbial Pathogenesis Section, Division of Intramural Research, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD 20892

Address correspondence to F. Gisou van der Goot, Dept. of Genetics and Microbiology, 1 rue Michel Servet, 1211 Geneva 4, Switzerland. Tel.: (41) 022-702-5652. Fax: (41) 022-702-5896. E-mail: gisou.vandergoot{at}medecine.unige.ch

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.

Key Words: anthrax toxin; rafts; microdomains; clustering; protective antigen


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