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Infection and Immunity, December 2009, p. 5471-5477, Vol. 77, No. 12
0019-9567/09/$08.00+0     doi:10.1128/IAI.00860-09
Copyright © 2009, American Society for Microbiology. All Rights Reserved.

The Enteropathogenic Escherichia coli Effector Cif Induces Delayed Apoptosis in Epithelial Cells{triangledown}

Ascel Samba-Louaka,1,2 Jean-Philippe Nougayrède,1,2 Claude Watrin,1,2 Eric Oswald,1,2,3,4 and Frédéric Taieb1,2*

INRA, UMR1225, F-31076 Toulouse, France,1 Université de Toulouse, ENVT, UMR 1225, F-31076 Toulouse, France,2 Université de Toulouse, UPS, Faculté de Médecine, Toulouse F-31400,3 Laboratoire de Bactériologie-Hygiene, CHU de Toulouse, Institut Fédératif de Biologie, Toulouse F-31059, France4

Received 30 July 2009/ Returned for modification 18 August 2009/ Accepted 18 September 2009

The cycle inhibiting factor (Cif) belongs to a family of bacterial toxins, the cyclomodulins, which modulate the host cell cycle. Upon injection into the host cell by the type III secretion system of enteropathogenic Escherichia coli (EPEC), Cif induces both G2 and G1 cell cycle arrests. The cell cycle arrests correlate with the accumulation of p21waf1 and p27kip1 proteins that inhibit CDK-cyclin complexes, whose activation is required for G1/S and G2/M transitions. Increases of p21 and p27 levels are independent of p53 transcriptional induction and result from protein stabilization through inhibition of the ubiquitin/proteasome degradation pathway. In this study, we show that Cif not only induces cell cycle arrest but also eventually provokes a delayed cell death. Indeed, 48 h after infection with EPEC expressing Cif, cultured IEC-6 intestinal cells were positive for extracellular binding of annexin V and exhibited high levels of cleaved caspase-3 and lactate dehydrogenase release, indicating evidence of apoptosis. Cif was necessary and sufficient for inducing this late apoptosis, and the cysteine residue of the catalytic site was required for Cif activity. These results highlight a more complex role of Cif than previously thought, as a cyclomodulin but also as an apoptosis inducer.

* Corresponding author. Mailing address: Université de Toulouse, ENVT, UMR 1225, F-31076 Toulouse, France. Phone and fax: 33 5 61 19 32 86. E-mail: f.taieb{at}envt.fr

{triangledown} Published ahead of print on 28 September 2009.

Editor: S. M. Payne

Infection and Immunity, December 2009, p. 5471-5477, Vol. 77, No. 12
0019-9567/09/$08.00+0     doi:10.1128/IAI.00860-09
Copyright © 2009, American Society for Microbiology. All Rights Reserved.





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