AB5 subtilase cytotoxin inactivates the endoplasmic reticulum chaperone BiP

Adrienne W. Paton (), Travis Beddoe, Cheleste M. Thorpe, James C. Whisstock, Matthew C. J. Wilce, Jamie Rossjohn, Ursula M. Talbot and James C. Paton ()
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Adrienne W. Paton: University of Adelaide
Travis Beddoe: Department of Biochemistry and Molecular Biology, Monash University
Cheleste M. Thorpe: Tufts-New England Medical Center
James C. Whisstock: Department of Biochemistry and Molecular Biology, Monash University
Matthew C. J. Wilce: Department of Biochemistry and Molecular Biology, Monash University
Jamie Rossjohn: Department of Biochemistry and Molecular Biology, Monash University
Ursula M. Talbot: University of Adelaide
James C. Paton: University of Adelaide

Nature, 2006, vol. 443, issue 7111, 548-552

Abstract: Abstract AB5 toxins are produced by pathogenic bacteria and consist of enzymatic A subunits that corrupt essential eukaryotic cell functions, and pentameric B subunits that mediate uptake into the target cell. AB5 toxins include the Shiga, cholera and pertussis toxins and a recently discovered fourth family, subtilase cytotoxin, which is produced by certain Shiga toxigenic strains of Escherichia coli. Here we show that the extreme cytotoxicity of this toxin for eukaryotic cells is due to a specific single-site cleavage of the essential endoplasmic reticulum chaperone BiP/GRP78. The A subunit is a subtilase-like serine protease; structural studies revealed an unusually deep active-site cleft, which accounts for its exquisite substrate specificity. A single amino-acid substitution in the BiP target site prevented cleavage, and co-expression of this resistant protein protected transfected cells against the toxin. BiP is a master regulator of endoplasmic reticulum function, and its cleavage by subtilase cytotoxin represents a previously unknown trigger for cell death.

Date: 2006
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DOI: 10.1038/nature05124

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