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Identification of the cellular receptor for anthrax toxin

Abstract

The tripartite toxin secreted by Bacillus anthracis, the causative agent of anthrax, helps the bacterium evade the immune system and can kill the host during a systemic infection. Two components of the toxin enzymatically modify substrates within the cytosol of mammalian cells: oedema factor (OF) is an adenylate cyclase that impairs host defences through a variety of mechanisms including inhibiting phagocytosis1,2; lethal factor (LF) is a zinc-dependent protease that cleaves mitogen-activated protein kinase kinase and causes lysis of macrophages3,4,5. Protective antigen (PA), the third component, binds to a cellular receptor and mediates delivery of the enzymatic components to the cytosol. Here we describe the cloning of the human PA receptor using a genetic complementation approach. The receptor, termed ATR (anthrax toxin receptor), is a type I membrane protein with an extracellular von Willebrand factor A domain that binds directly to PA. In addition, a soluble version of this domain can protect cells from the action of the toxin.

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Figure 1: Mutant CHO-R1.1 cells display a decreased OGPA-binding phenotype that can be corrected by overexpression of the ATR cDNA.
Figure 2: Sequence alignment of ATR with the I domain of integrin α2 (α2-I), the von Willebrand factor A domain consensus sequence (VWA-CON, generated from 210 sequences aligned by the National Center for Biotechnology Information), and TEM8.
Figure 3: The VWA/I domain of ATR binds directly to PA.
Figure 4: T7–ATR41–227 protects cells from killing by PA with LFN–DTA.

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Acknowledgements

We thank K. Schell and members of the flow cytometry facility at the University of Wisconsin Comprehensive Cancer Center for performing the cell sorting. This work was supported by a grant to J.A.T.Y. and R.J.C. from the National Institutes of Health. J.M. was supported in part by a Medical Research Council (Canada) postdoctoral fellowship.

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R.J.C. holds financial interest in AVANT Immunotherapeutics and PharmAthene, Inc.

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Bradley, K., Mogridge, J., Mourez, M. et al. Identification of the cellular receptor for anthrax toxin. Nature 414, 225–229 (2001). https://doi.org/10.1038/n35101999

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