The Enteropathogenic Escherichia coli Effector Cif Induces Delayed Apoptosis in Epithelial Cells
- 1 December 2009
- journal article
- research article
- Published by American Society for Microbiology in Infection and Immunity
- Vol. 77 (12), 5471-5477
- https://doi.org/10.1128/iai.00860-09
Abstract
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 G 2 and G 1 cell cycle arrests. The cell cycle arrests correlate with the accumulation of p21 waf1 and p27 kip1 proteins that inhibit CDK-cyclin complexes, whose activation is required for G 1 /S and G 2 /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.Keywords
This publication has 39 references indexed in Scilit:
- Crystal Structures of Cif from Bacterial Pathogens Photorhabdus luminescens and Burkholderia pseudomalleiPLOS ONE, 2009
- Cycle Inhibiting Factors (CIFs) Are a Growing Family of Functional Cyclomodulins Present in Invertebrate and Mammal Bacterial PathogensPLOS ONE, 2009
- A bacterial type III effector family uses the papain-like hydrolytic activity to arrest the host cell cycleProceedings of the National Academy of Sciences of the United States of America, 2009
- The effector repertoire of enteropathogenic E. coli: ganging up on the host cellCurrent Opinion in Microbiology, 2009
- Structure of the Cyclomodulin Cif from Pathogenic Escherichia coliJournal of Molecular Biology, 2008
- Distribution, Functional Expression, and Genetic Organization of Cif, a Phage-Encoded Type III-Secreted Effector from Enteropathogenic and EnterohemorrhagicEscherichia coliJournal of Bacteriology, 2008
- Escherichia coli cyclomodulin Cif induces G2arrest of the host cell cycle without activation of the DNA-damage checkpoint-signalling pathwayCellular Microbiology, 2006
- Bacterial toxins that modulate host cell-cycle progressionCurrent Opinion in Microbiology, 2005
- Targeting of Enteropathogenic Escherichia coli EspF to Host Mitochondria Is Essential for Bacterial PathogenesisJournal of Biological Chemistry, 2005
- Type III Secretion-Dependent Cell Cycle Block Caused in HeLa Cells by Enteropathogenic Escherichia coli O103Infection and Immunity, 2001