Rho GTPase-activating bacterial toxins: from bacterial virulence regulation to eukaryotic cell biology

Lemonnier, Marguerite; Landraud, Luce; Lemichez, Emmanuel

doi:10.1111/j.1574-6976.2007.00078.x

Cited by 81 publications

(95 citation statements)

References 165 publications

(362 reference statements)

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“…CNF1 is a cytoplasmic protein, and its secretion is a strategy utilized by meningitis-causing E. coli K1 to invade the blood-brain barrier (12). CNF1 is the paradigm of the RhoGTPase-activating bacterial toxins (2,19). The CNF1 secretion pathway, however, remains incompletely understood.…”

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confidence: 99%

Ferredoxin Is Involved in Secretion of Cytotoxic Necrotizing Factor 1 across the Cytoplasmic Membrane in Escherichia coli K1

Kim

2010

Infect Immun

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We previously showed that cytotoxic necrotizing factor 1 (CNF1) contributes to Escherichia coli K1 invasion of human brain microvascular endothelial cells (HBMEC) and interacts with the receptor on the surface of HBMEC. CNF1 is the cytoplasmic protein, and it remains incompletely understood how CNF1 is secreted across the inner and outer membranes in E. coli K1. In order to investigate the genetic determinants for secretion of CNF1 in E. coli K1, we performed Tn5 mutagenesis screening by applying ␤-lactamase as a reporter to monitor secretion of CNF1. We identified a Tn5 mutant that exhibited no ␤-lactamase activity in the culture supernatant and in which the mutated gene encodes a ferredoxin gene (fdx). In the fdx deletion mutant, there was no evidence of translocation of CNF1 into HBMEC. Western blot analysis of the fdx deletion mutant revealed that ferredoxin is involved in translocation of CNF1 across the cytoplasmic membrane. The fdx mutant exhibited significantly decreased invasion of HBMEC, similar to the decreased HBMEC invasion observed with the CNF1 mutant. The failures to secrete CNF1 and invade HBMEC of the fdx mutant were restored to the levels of the parent strain by complementation with fdx. These findings demonstrate for the first time that ferredoxin is involved in secretion of CNF1 across the inner membrane in meningitis-causing E. coli K1.Neonatal Escherichia coli meningitis is associated with high mortality and morbidity, and a major contributing factor is our incomplete knowledge on the pathogenesis of E. coli meningitis (15, 16). Most cases of neonatal E. coli meningitis develop as a result of hematogenous spread (8, 14), but it is incompletely understood how circulating bacteria cross the bloodbrain barrier and cause meningitis.We have shown that cytotoxic necrotizing factor 1 (CNF1) contributes to E. coli K1 invasion of human brain microvascular endothelial cells (HBMEC) and penetration into the central nerve system (CNS) via the interaction with its receptor, 37 laminin receptor precursor (37LRP)/67 laminin receptor (67LR) (4, 12, 13). CNF1 is a cytoplasmic protein, and its secretion is a strategy utilized by meningitis-causing E. coli K1 to invade the blood-brain barrier (12). CNF1 is the paradigm of the RhoGTPase-activating bacterial toxins (2, 19). The CNF1 secretion pathway, however, remains incompletely understood. No typical signal peptide is found in the CNF1 sequence. A previous study by Kouokam et al. showed that CNF1 is tightly associated with outer membrane vesicles (18). Outer membrane vesicles from a number of bacterial species have been found to contain virulence factors, exhibit immunomodulatory effects, and adhere to and intoxicate host cells (20).In order to study the genetic determinants for secretion of CNF1 in meningitis-causing E. coli K1, we designed a Tn5 mutational screening strategy by applying TEM ␤-lactamase as the reporter. Using this approach, we identified a mutant which was defective in CNF1 secretion into HBMEC, and this mutant is characterized in this rep...

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Ferredoxin Is Involved in Secretion of Cytotoxic Necrotizing Factor 1 across the Cytoplasmic Membrane in Escherichia coli K1

Kim

2010

Infect Immun

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“…In the species E. coli, four kinds of CMs have been identified: the rho GTPase-targeting toxins CNF-1 to CNF-3 (cytotoxic necrotizing factors) (34), the cycle-inhibiting factor (Cif) (38), and two kinds of genotoxins, cytolethal distending toxins (CDTs) I to V (19) and the recently discovered colibactin (41). Colibactin is probably a hybrid polyketidenonribosomal peptide toxin, whose activity is encoded by the genomic pks island (41).…”

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Cyclomodulins in Urosepsis Strains of Escherichia coli

et al. 2010

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Determinants of urosepsis in Escherichia coli remain incompletely defined. Cyclomodulins (CMs) are a growing functional family of toxins that hijack the eukaryotic cell cycle. Four cyclomodulin types are actually known in E. coli: cytotoxic necrotizing factors (CNFs), cycle-inhibiting factor (Cif), cytolethal distending toxins (CDTs), and the pks-encoded toxin. In the present study, the distribution of CM-encoding genes and the functionality of these toxins were investigated in 197 E. coli strains isolated from patients with communityacquired urosepsis (n ‫؍‬ 146) and from uninfected subjects (n ‫؍‬ 51). This distribution was analyzed in relation to the phylogenetic background, clinical origin, and antibiotic resistance of the strains. It emerged from this study that strains harboring the pks island and the cnf1 gene (i) were strongly associated with the B2 phylogroup (P, <0.001), (ii) frequently harbored both toxin-encoded genes in phylogroup B2 (33%), and (iii) were predictive of a urosepsis origin (P, <0.001 to 0.005). However, the prevalences of the pks island among phylogroup B2 strains, in contrast to those of the cnf1 gene, were not significantly different between fecal and urosepsis groups, suggesting that the pks island is more important for the colonization process and the cnf1 gene for virulence. pks-or cnf1-harboring strains were significantly associated with susceptibility to antibiotics (amoxicillin, cotrimoxazole, and quinolones [P, <0.001 to 0.043]). Otherwise, only 6% and 1% of all strains harbored the cdtB and cif genes, respectively, with no particular distribution by phylogenetic background, antimicrobial susceptibility, or clinical origin.The bacterial species Escherichia coli comprises a wide diversity of strains belonging to the commensal intestinal flora of humans and warm-blooded animals. Among these strains, several pathogenic variants cause intestinal or extraintestinal infections in humans and animals (33). Population genetic studies based on multilocus enzyme electrophoresis and various DNA markers (10,20,44) classify the E. coli strains into four major phylogenetic groups (A, B1, B2, and D). The groups are diversely associated with certain ecological niches and propensities to cause disease.Extraintestinal pathogenic E. coli (ExPEC) strains are facultative pathogens that are not yet fully described. They are reported to belong mainly to phylogroups B2 and D, and they possess high numbers of virulence genes that belong to a flexible gene pool (43, 53). Among ExPEC strains, uropathogenic E. coli (UPEC) strains take advantage of host behavior and susceptibility by employing virulence factors that facilitate bacterial growth and persistence in the urinary tract (5, 28-30). Important virulence mechanisms are adhesion, invasion, subversion of host defenses, and direct interference with host cellular functions via secreted effectors (33,69).These effectors include the cyclomodulins (CMs), a functional class of toxins that hijack the cell cycle, a fundamental host cell process (48). In the ...

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“…CNF1 is a Rho GTPases-targeting toxin that deamidates the glutamine in position 61 of Rac and Cdc42, as well as the equivalent glutamine 63 of RhoA, destroying the GTPase activity and thereby locking them into an active form. [4][5][6] CNF1 shows structural and functional homologies with factors found in other pathogenic bacterial species. This includes CNF2 from E. coli, CNFy from Yersinia pseudotuberculosis and DNT from Bordetella spp.…”

Section: Introductionmentioning

confidence: 99%

“…This includes CNF2 from E. coli, CNFy from Yersinia pseudotuberculosis and DNT from Bordetella spp. 4 . More recently, the effector VopC from Vibrio parahaemolyticus that is injected through a TTS3 secretion system was found to deamidate Rac1 and Cdc42.…”

Section: Introductionmentioning

confidence: 99%

Switching Rho GTPase activation into effective antibacterial defenses requires the caspase-1/IL-1beta signaling axis

Boyer

Lemichez²

2015

Small GTPases

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Rho GTPase-activating bacterial toxins: from bacterial virulence regulation to eukaryotic cell biology

Cited by 81 publications

References 165 publications

Ferredoxin Is Involved in Secretion of Cytotoxic Necrotizing Factor 1 across the Cytoplasmic Membrane in Escherichia coli K1

Ferredoxin Is Involved in Secretion of Cytotoxic Necrotizing Factor 1 across the Cytoplasmic Membrane in Escherichia coli K1

Cyclomodulins in Urosepsis Strains of Escherichia coli

Switching Rho GTPase activation into effective antibacterial defenses requires the caspase-1/IL-1beta signaling axis

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