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Vol. 18, Issue 7, 2735-2744, July 2007

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Cytotoxic Necrotizing Factor 1 Prevents Apoptosis via the Akt/IB Kinase Pathway: Role of Nuclear Factor-B and Bcl-2

Alessandro Giamboi Miraglia^*, Sara Travaglione^*, Stefania Meschini, Loredana Falzano^*, Paola Matarrese^*, Maria Giovanna Quaranta^*, Marina Viora^*, Carla Fiorentini^*,, and Alessia Fabbri^*,

Departments of *Drug Research and Evaluation and Technology and Health, Istituto Superiore di Sanità, 00161 Rome, Italy

Submitted October 11, 2006; Revised March 28, 2007; Accepted May 3, 2007
Monitoring Editor: Ralph Isberg

Cytotoxic necrotizing factor 1 (CNF1) is a protein toxin produced by some pathogenic strains of Escherichia coli that specifically activates Rho, Rac, and Cdc42 GTPases. We previously reported that this toxin prevents the ultraviolet-B–induced apoptosis in epithelial cells, with a mechanism that remained to be defined. In this work, we show that the proteasomal degradation of the Rho GTPase is necessary to achieve cell death protection, because inhibition of Rho degradation abolishes the prosurvival activity of CNF1. We hypothesize that Rho inactivation allows the activity of Rac to become dominant. This in turn leads to stimulation of the phosphoinositide 3-kinase/Akt/IB kinase/nuclear factor-B prosurvival pathway and to a remarkable modification in the architecture of the mitochondrial network, mainly consisting in the appearance of elongated and interconnected mitochondria. Importantly, we found that Bcl-2 silencing reduces the ability of CNF1 to protect cells against apoptosis and that it also prevents the CNF1-induced mitochondrial changes. It is worth noting that the ability of a bacterial toxin to induce such a remodeling of the mitochondrial network is herein reported for the first time. The possible pathophysiological relevance of this finding is discussed.

The online version of this article contains supplemental material at MBC Online (http://www.molbiolcell.org).

C.F. and A.F. were principal investigators.

Address correspondence to: Carla Fiorentini (carla.fiorentini{at}iss.it)

Abbreviations used: CNF1, cytotoxic necrotizing factor 1; FITC, fluorescein isothiocyanate; IKK, IB kinase; NF-B, nuclear factor-B; PGA1, prostaglandin A1; PI3K, phosphoinositide 3-kinase; TBS-T, Tris-buffered saline-Tween 20.

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