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.
Skip Nav Destination
Article navigation
3 February 2003
Report|
January 27 2003
Anthrax toxin triggers endocytosis of its receptor via a lipid raft–mediated clathrin-dependent process
Laurence Abrami,
Laurence Abrami
1Department of Genetics and Microbiology, University of Geneva, 1211 Geneva 4, Switzerland
Search for other works by this author on:
Shihui Liu,
Shihui Liu
3Microbial Pathogenesis Section, Division of Intramural Research, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD 20892
Search for other works by this author on:
Pierre Cosson,
Pierre Cosson
2Department of Morphology, University of Geneva, 1211 Geneva 4, Switzerland
Search for other works by this author on:
Stephen H. Leppla,
Stephen H. Leppla
3Microbial Pathogenesis Section, Division of Intramural Research, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD 20892
Search for other works by this author on:
F. Gisou van der Goot
F. Gisou van der Goot
1Department of Genetics and Microbiology, University of Geneva, 1211 Geneva 4, Switzerland
Search for other works by this author on:
Laurence Abrami
1Department of Genetics and Microbiology, University of Geneva, 1211 Geneva 4, Switzerland
Shihui Liu
3Microbial Pathogenesis Section, Division of Intramural Research, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD 20892
Pierre Cosson
2Department of Morphology, University of Geneva, 1211 Geneva 4, Switzerland
Stephen H. Leppla
3Microbial Pathogenesis Section, Division of Intramural Research, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD 20892
F. Gisou van der Goot
1Department of Genetics and Microbiology, University of Geneva, 1211 Geneva 4, Switzerland
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: [email protected]
*
Abbreviations used in this paper: ATR, anthrax toxin receptor; ATR-HA, COOH-terminal HA epitope-tagged version of ATR; β-MCD, β-methyl cyclodextrin; DRM, detergent-resistant membrane; EF, edema factor; LF, lethal factor; PA, protective antigen; PA63, COOH-terminal 63-kD moiety; PA83, protective antigen of 83-kD; PASNKE, PA mutated in the consensus furin cleavage site.
Received:
November 05 2002
Revision Received:
December 11 2002
Accepted:
December 13 2002
Online ISSN: 1540-8140
Print ISSN: 0021-9525
The Rockefeller University Press
2003
J Cell Biol (2003) 160 (3): 321–328.
Article history
Received:
November 05 2002
Revision Received:
December 11 2002
Accepted:
December 13 2002
Citation
Laurence Abrami, Shihui Liu, Pierre Cosson, Stephen H. Leppla, F. Gisou van der Goot; Anthrax toxin triggers endocytosis of its receptor via a lipid raft–mediated clathrin-dependent process . J Cell Biol 3 February 2003; 160 (3): 321–328. doi: https://doi.org/10.1083/jcb.200211018
Download citation file:
Sign in
Don't already have an account? Register
Client Account
You could not be signed in. Please check your email address / username and password and try again.
Could not validate captcha. Please try again.
Sign in via your Institution
Sign in via your InstitutionEmail alerts
Advertisement
Advertisement