IAI Accepts, published online ahead of print on 23 February 2009

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Infect. Immun. doi:10.1128/IAI.01145-08
Copyright (c) 2009, American Society for Microbiology and/or the Listed Authors/Institutions. All Rights Reserved.

Cleavage of the Escherichia coli Cytotoxic Necrotizing Factor 1 (CNF1) is Required for Full Biologic Activity

Zeynep Knust, Britta Blumenthal, Klaus Aktories, and Gudula Schmidt^*

Institut für Experimentelle und Klinische Pharmakologie und Toxikologie der Albert-Ludwigs-Universität Freiburg, Albert-Str. 25, 79104 Freiburg, Germany; Fakultät für Biologie, Albert-Ludwigs-Universität Freiburg, Germany

^* To whom correspondence should be addressed. Email: Gudula.Schmidt{at}pharmakol.uni-freiburg.de.

The cytotoxic necrotizing factor 1 (CNF1) is a protein toxin produced by pathogenic Escherichia coli strains. CNF1 constitutively activates small GTPases of the Rho family by deamidation of a glutamine, which is crucial for GTP hydrolysis. The toxin is taken up into mammalian cells by receptor-mediated endocytosis and is delivered from late endosomes into the cytosol. Here, we show that an approximately 55 kDa fragment of CNF1, which contains the catalytic domain and an additional part of the toxin, is present in the cytosol. Its processing requires an acidic pH and insertion of the toxin into the endosomal membrane. We define the cleavage site region to be located between amino acid 532 and 544 of CNF1. The data provide insight into the complex uptake mechanism of bacterial toxins into mammalian cells.