title: Cytotoxic necrotizing factor 1 prevents apoptosis via the Akt/IkappaB kinase pathway: role of nuclear factor-kappaB and Bcl-2.
abstract: 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/IkappaB kinase/nuclear factor-kappaB 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.
authors.affiliation: Departments of Drug Research and Evaluation and Technology, Istituto Superiore di Sanità, Rome, Italy.
authors.forename: Alessandro Giamboi
authors.initials: AG
authors.lastname: Miraglia
authors.forename: Sara
authors.initials: S
authors.lastname: Travaglione
authors.forename: Stefania
authors.initials: S
authors.lastname: Meschini
authors.forename: Loredana
authors.initials: L
authors.lastname: Falzano
authors.forename: Paola
authors.initials: P
authors.lastname: Matarrese
authors.forename: Maria Giovanna
authors.initials: MG
authors.lastname: Quaranta
authors.forename: Marina
authors.initials: M
authors.lastname: Viora
authors.forename: Carla
authors.initials: C
authors.lastname: Fiorentini
authors.forename: Alessia
authors.initials: A
authors.lastname: Fabbri
mesh_terms: D017209:Apoptosis / Q000187:drug effects* / Q000528:radiation effects; D001427:Bacterial Toxins / Q000494:pharmacology*; D002460:Cell Line; D002470:Cell Survival / Q000187:drug effects / Q000528:radiation effects; D004789:Enzyme Activation / Q000187:drug effects / Q000528:radiation effects; D004847:Epithelial Cells / Q000166:cytology / Q000187:drug effects / Q000528:radiation effects; D029968:Escherichia coli Proteins / Q000494:pharmacology*; D006801:Humans; D051550:I-kappa B Kinase / Q000378:metabolism*; D007700:Kinetics; D008928:Mitochondria / Q000187:drug effects / Q000528:radiation effects; D008954:Models, Biological; D016328:NF-kappa B / Q000378:metabolism*; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism*; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000235:genetics / Q000378:metabolism*; D014158:Transcription, Genetic / Q000187:drug effects / Q000528:radiation effects; D014466:Ultraviolet Rays; D051020:bcl-X Protein / Q000378:metabolism; D020830:rac1 GTP-Binding Protein / Q000378:metabolism; D020741:rho GTP-Binding Proteins / Q000378:metabolism
chemical_list: D001427:Bacterial Toxins; D029968:Escherichia coli Proteins; D016328:NF-kappa B; D019253:Proto-Oncogene Proteins c-bcl-2; D051020:bcl-X Protein; C060296:cytotoxic necrotizing factor type 1; D019869:Phosphatidylinositol 3-Kinases; D051057:Proto-Oncogene Proteins c-akt; D051550:I-kappa B Kinase; D020830:rac1 GTP-Binding Protein; D020741:rho GTP-Binding Proteins