Cycle Inhibiting Factors (Cifs): Cyclomodulins That Usurp the Ubiquitin-Dependent Degradation Pathway of Host Cells

Frédéric Taieb,Eric Oswald,Jean-Philippe Nougayrède

doi:10.3390/toxins3040356

Abstract

Cycle inhibiting factors (Cifs) are type III secreted effectors produced by diverse pathogenic bacteria. Cifs are “cyclomodulins” that inhibit the eukaryotic host cell cycle and also hijack other key cellular processes such as those controlling the actin network and apoptosis. This review summarizes current knowledge on Cif since its first characterization in enteropathogenic Escherichia coli, the identification of several xenologues in distant pathogenic bacteria, to its structure elucidation and the recent deciphering of its mode of action. Cif impairs the host ubiquitin proteasome system through deamidation of ubiquitin or the ubiquitin-like protein NEDD8 that regulates Cullin-Ring-ubiquitin Ligase (CRL) complexes. The hijacking of the ubiquitin-dependent degradation pathway of host cells results in the modulation of various cellular functions such as epithelium renewal, apoptosis and immune response. Cif is therefore a powerful weapon in the continuous arm race that characterizes host-bacteria interactions.

Highlights

Cycle inhibiting factors (Cifs) are type III secreted effectors produced by diverse pathogenic bacteria
The effect of Cif was first observed in 1997 by De Rycke et al in HeLa cells transiently infected with enteropathogenic Escherichia coli (EPEC) strains isolated from weaning rabbits or human infants with diarrhea [1]
It was further shown that these large cells were irreversibly impaired for cell proliferation, with a complete lack of mitotic figures [2] (Figure 1). This effect is dependent on the locus of enterocyte effacement (LEE), the cluster of genes responsible for the attaching and effacing lesion, the hallmark of EPEC and enterohemorraghic E. coli (EHEC) infection [3,4]

Summary

Cifs Are Cyclomodulins That Trigger Host Cell Cycle Arrest

Upon injection into host cells by the T3SS (or by transfection or lipofection of purified proteins) Cif proteins induce an irreversible cell cycle arrest with complete inhibition of mitotis entry (Figure 1: absence of mitotic figures in cells injected with Cif). The cell cycle arrest induced by CifEc is associated to the inhibitory phosphorylation of the cyclin dependent kinase (CDK) 1-CyclinB complex whose activation is necessary for the cell cycle G2/M transition [1,2,5]. The analysis of host cell proteins regulating both S- and M- phases entries demonstrated a Cif-dependent accumulation of p21Waf1/Cip and p27kip (hereafter called p21 and p27) [24] These proteins belong to the Cip/Kip family of CDK inhibitors (CKI). HeLa and RK13 cells exhibit stress fibers following cif+ EPEC infection suggesting that these two phenotypes are not related [16] These results indicated that accumulation of CKI participates in a multi-step process leading to the Cif-induced arrest of cell proliferation. Despite few differences mainly related to the species origin of Cif and diverse approaches, these complementary studies showed a common mechanism of action between the two xenologs

CifEc Interacts with Host Protein NEDD8

Cif Inhibits CRL Activity

Findings

Concluding remarks and perspectives