The cytotoxic necrotizing factor 1 from E. coli: a janus toxin playing with cancer regulators - PubMed (original) (raw)

Review

The cytotoxic necrotizing factor 1 from E. coli: a janus toxin playing with cancer regulators

Alessia Fabbri et al. Toxins (Basel). 2013.

Abstract

Certain strains of Escherichia coli have been indicated as a risk factor for colon cancer. E. coli is a normal inhabitant of the human intestine that becomes pathogenic, especially in extraintestinal sites, following the acquisition of virulence factors, including the protein toxin CNF1. This Rho GTPases-activating toxin induces dysfunctions in transformed epithelial cells, such as apoptosis counteraction, pro-inflammatory cytokines' release, COX2 expression, NF-kB activation and boosted cellular motility. As cancer may arise when the same regulatory pathways are affected, it is conceivable to hypothesize that CNF1-producing E. coli infections can contribute to cancer development. This review focuses on those aspects of CNF1 related to transformation, with the aim of contributing to the identification of a new possible carcinogenic agent from the microbial world.

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Figures

Figure 1

Figure 1

Mechanism of action of CNF1. CNF1 is a single chain multidomain protein toxin that contains a binding domain at the _N_-terminus, a central translocation domain, and an enzymatic domain at _C_-terminus. CNF1 exerts its deamidating activity on a glutamine residue located in the switch 2 domain of the Rho GTPases, essential for the molecule inactivation by GTP hydrolysis. CNF1, by modifying glutamine into glutamic acid, stabilizes the G proteins in their GTP-bound active form enabling them to exert a permanent activity on their effectors. By activating these GTPase, CNF1 stimulates the actin cytoskeleton, fostering a prominent ruffling activity. The activated Rho GTPases are subsequently recognized for ubiquitylation and degraded in the proteasome.

Figure 2

Figure 2

Signalling pathways triggered by CNF1-promoted Rho activation differ depending on the cell type. (A) In CNF1-challenged transformed cells, NF-kB translocates from cytoplasm to nucleus where it leads to the expression of pro-inflammatory and anti-apoptotic factors. Modulation of the actin cytoskeleton via the CNF1-activated Rho GTPases also plays a crucial role in certain aspects of the malignant phenotype. In particular, CNF1 induces: tumour cell motility, modification of cellular shape, loss of adhesion with consequent invasiveness and metastasis, an asymmetric cell division and aneuploidy. Furthermore, CNF1 provokes mitochondrial release of reactive oxygen species (ROS) with consequent pro-inflammatory cytokines expression. (B) In primary brain cells, through a cytoskeleton modulation, CNF1 acts on mitochondrial activity, boosts cellular ATP content, decreases pro-inflammatory cytokines expression, and increments synaptic plasticity. This leads, in vivo, to an enhancement of brain functional performances.

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