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Cycle inhibiting factors (CIFs) are a growing family of functional cyclomodulins present in invertebrate and mammal bacterial pathogens.

Jubelin G, Chavez CV, Taieb F, Banfield MJ, Samba-Louaka A, Nobe R, Nougayr├Ęde JP, Zumbihl R, Givaudan A, Escoubas JM, Oswald E - PLoS ONE (2009)

Bottom Line: The cycle inhibiting factor (Cif) produced by enteropathogenic and enterohemorrhagic Escherichia coli was the first cyclomodulin to be identified that is injected into host cells via the type III secretion machinery.The X-ray crystal structure of Cif revealed it to be a divergent member of a superfamily of enzymes including cysteine proteases and acetyltransferases that share a conserved catalytic triad.Cif homologs from the enterobacteria Yersinia pseudotuberculosis, Photorhabdus luminescens, Photorhabdus asymbiotica and the beta-proteobacterium Burkholderia pseudomallei all induce cytopathic effects identical to those observed with Cif from pathogenic E. coli.

View Article: PubMed Central - PubMed

Affiliation: INRA, UMR1225, Toulouse, France.

ABSTRACT
The cycle inhibiting factor (Cif) produced by enteropathogenic and enterohemorrhagic Escherichia coli was the first cyclomodulin to be identified that is injected into host cells via the type III secretion machinery. Cif provokes cytopathic effects characterized by G(1) and G(2) cell cycle arrests, accumulation of the cyclin-dependent kinase inhibitors (CKIs) p21(waf1/cip1) and p27(kip1) and formation of actin stress fibres. The X-ray crystal structure of Cif revealed it to be a divergent member of a superfamily of enzymes including cysteine proteases and acetyltransferases that share a conserved catalytic triad. Here we report the discovery and characterization of four Cif homologs encoded by different pathogenic or symbiotic bacteria isolated from vertebrates or invertebrates. Cif homologs from the enterobacteria Yersinia pseudotuberculosis, Photorhabdus luminescens, Photorhabdus asymbiotica and the beta-proteobacterium Burkholderia pseudomallei all induce cytopathic effects identical to those observed with Cif from pathogenic E. coli. Although these Cif homologs are remarkably divergent in primary sequence, the catalytic triad is strictly conserved and was shown to be crucial for cell cycle arrest, cytoskeleton reorganization and CKIs accumulation. These results reveal that Cif proteins form a growing family of cyclomodulins in bacteria that interact with very distinct hosts including insects, nematodes and humans.

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Cif homologs induce p21 and p27 accumulation in cells.HeLa cells were treated with PBS or purified Cif proteins (wild-type (WT) or cysteine variants (C/S) as indicated), in combination with BioPORTER. Cell extracts were probed with anti-p21, anti-p27 and anti-actin antibodies 24 h post-treatment.
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pone-0004855-g008: Cif homologs induce p21 and p27 accumulation in cells.HeLa cells were treated with PBS or purified Cif proteins (wild-type (WT) or cysteine variants (C/S) as indicated), in combination with BioPORTER. Cell extracts were probed with anti-p21, anti-p27 and anti-actin antibodies 24 h post-treatment.

Mentions: It has recently been shown that the cytopathic activity of CifEc is correlated to the accumulation of CKIs p21 and p27, two important regulators of cell cycle progression [6]. Since all Cif homologs appear to share the same catalytic triad and induce identical cytopathic phenotypes in HeLa cells, we wonder if they could hijack the same signaling pathways, despite the fact that two of these proteins are produced by bacteria colonizing insects and nematodes. Western-blot analysis of HeLa cells treated with purified Cif homologs indicated that levels of p21 and p27 increase in the presence of wild-type CifBp, CifPl and CifPa (Fig. 8). An intact catalytic triad is integral to this accumulation as CKIs levels were not affected when cells were treated with the cysteine variants (Fig. 8). This accumulation of p21 and p27 suggests that the molecular mechanisms involved in Cif cytotoxicity on HeLa cells are identical for CifEc and the Cif homologs.


Cycle inhibiting factors (CIFs) are a growing family of functional cyclomodulins present in invertebrate and mammal bacterial pathogens.

Jubelin G, Chavez CV, Taieb F, Banfield MJ, Samba-Louaka A, Nobe R, Nougayr├Ęde JP, Zumbihl R, Givaudan A, Escoubas JM, Oswald E - PLoS ONE (2009)

Cif homologs induce p21 and p27 accumulation in cells.HeLa cells were treated with PBS or purified Cif proteins (wild-type (WT) or cysteine variants (C/S) as indicated), in combination with BioPORTER. Cell extracts were probed with anti-p21, anti-p27 and anti-actin antibodies 24 h post-treatment.
© Copyright Policy
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC2654923&req=5

pone-0004855-g008: Cif homologs induce p21 and p27 accumulation in cells.HeLa cells were treated with PBS or purified Cif proteins (wild-type (WT) or cysteine variants (C/S) as indicated), in combination with BioPORTER. Cell extracts were probed with anti-p21, anti-p27 and anti-actin antibodies 24 h post-treatment.
Mentions: It has recently been shown that the cytopathic activity of CifEc is correlated to the accumulation of CKIs p21 and p27, two important regulators of cell cycle progression [6]. Since all Cif homologs appear to share the same catalytic triad and induce identical cytopathic phenotypes in HeLa cells, we wonder if they could hijack the same signaling pathways, despite the fact that two of these proteins are produced by bacteria colonizing insects and nematodes. Western-blot analysis of HeLa cells treated with purified Cif homologs indicated that levels of p21 and p27 increase in the presence of wild-type CifBp, CifPl and CifPa (Fig. 8). An intact catalytic triad is integral to this accumulation as CKIs levels were not affected when cells were treated with the cysteine variants (Fig. 8). This accumulation of p21 and p27 suggests that the molecular mechanisms involved in Cif cytotoxicity on HeLa cells are identical for CifEc and the Cif homologs.

Bottom Line: The cycle inhibiting factor (Cif) produced by enteropathogenic and enterohemorrhagic Escherichia coli was the first cyclomodulin to be identified that is injected into host cells via the type III secretion machinery.The X-ray crystal structure of Cif revealed it to be a divergent member of a superfamily of enzymes including cysteine proteases and acetyltransferases that share a conserved catalytic triad.Cif homologs from the enterobacteria Yersinia pseudotuberculosis, Photorhabdus luminescens, Photorhabdus asymbiotica and the beta-proteobacterium Burkholderia pseudomallei all induce cytopathic effects identical to those observed with Cif from pathogenic E. coli.

View Article: PubMed Central - PubMed

Affiliation: INRA, UMR1225, Toulouse, France.

ABSTRACT
The cycle inhibiting factor (Cif) produced by enteropathogenic and enterohemorrhagic Escherichia coli was the first cyclomodulin to be identified that is injected into host cells via the type III secretion machinery. Cif provokes cytopathic effects characterized by G(1) and G(2) cell cycle arrests, accumulation of the cyclin-dependent kinase inhibitors (CKIs) p21(waf1/cip1) and p27(kip1) and formation of actin stress fibres. The X-ray crystal structure of Cif revealed it to be a divergent member of a superfamily of enzymes including cysteine proteases and acetyltransferases that share a conserved catalytic triad. Here we report the discovery and characterization of four Cif homologs encoded by different pathogenic or symbiotic bacteria isolated from vertebrates or invertebrates. Cif homologs from the enterobacteria Yersinia pseudotuberculosis, Photorhabdus luminescens, Photorhabdus asymbiotica and the beta-proteobacterium Burkholderia pseudomallei all induce cytopathic effects identical to those observed with Cif from pathogenic E. coli. Although these Cif homologs are remarkably divergent in primary sequence, the catalytic triad is strictly conserved and was shown to be crucial for cell cycle arrest, cytoskeleton reorganization and CKIs accumulation. These results reveal that Cif proteins form a growing family of cyclomodulins in bacteria that interact with very distinct hosts including insects, nematodes and humans.

Show MeSH
Related in: MedlinePlus