Cleavage of
            <i>Escherichia coli</i>
            Cytotoxic Necrotizing Factor 1 Is Required for Full Biologic Activity

Knust, Zeynep; Blumenthal, Britta; Aktories, Klaus; Schmidt, Gudula

doi:10.1128/iai.01145-08

Cited by 41 publications

(46 citation statements)

References 19 publications

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“…In these toxins, proteolytic nicking and integrity of the disulphide bond linking the A and B domains are essential for toxicity [19], [35], [36], [75]–[77]. In contrast, AIP56 toxicity is abolished by proteolytic nicking and only mildly compromised by disruption of the disulphide bridge by alkylation.…”

Section: Discussionmentioning

confidence: 99%

The Apoptogenic Toxin AIP56 Is a Metalloprotease A-B Toxin that Cleaves NF-κb P65

et al. 2013

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AIP56 (apoptosis-inducing protein of 56 kDa) is a major virulence factor of Photobacterium damselae piscicida (Phdp), a Gram-negative pathogen that causes septicemic infections, which are among the most threatening diseases in mariculture. The toxin triggers apoptosis of host macrophages and neutrophils through a process that, in vivo, culminates with secondary necrosis of the apoptotic cells contributing to the necrotic lesions observed in the diseased animals. Here, we show that AIP56 is a NF-κB p65-cleaving zinc-metalloprotease whose catalytic activity is required for the apoptogenic effect. Most of the bacterial effectors known to target NF-κB are type III secreted effectors. In contrast, we demonstrate that AIP56 is an A-B toxin capable of acting at distance, without requiring contact of the bacteria with the target cell. We also show that the N-terminal domain cleaves NF-κB at the Cys39-Glu40 peptide bond and that the C-terminal domain is involved in binding and internalization into the cytosol.

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Section: Discussionmentioning

confidence: 99%

The Apoptogenic Toxin AIP56 Is a Metalloprotease A-B Toxin that Cleaves NF-κb P65

et al. 2013

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“…However, we cannot exclude that a specific proteolytic step is involved in the translocation and/or action of PMT. In this respect, it is interesting that CNF1, which exhibits sequence similarity with PMT over a large N-terminal region, is apparently proteolytically processed during its cellular uptake (50). Whether this is also true for PMT remains to be analyzed.…”

Section: Discussionmentioning

confidence: 99%

Pasteurella multocida Toxin as a Transporter of Non-Cell-Permeating Proteins

et al. 2013

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bThe protein toxin Pasteurella multocida toxin (PMT) is the causative agent of atrophic rhinitis in pigs, leading to atrophy of the nasal turbinate bones by affecting osteoblasts and osteoclasts. The mechanism of PMT-induced intoxication is a deamidation of ␣-subunits of heterotrimeric G proteins, including G␣ q , G␣ 13 , and G␣ i , thereby causing persistent activation of the G proteins. Here we utilized PMT as a transporter of the non-cell-permeating A domain of diphtheria toxin (DTa). Fusion proteins of PMT and DTa ADP-ribosylated elongation factor 2, the natural target of diphtheria toxin, leading to cell toxicity. PMT-DTa effects were competed by PMT, indicating binding to the same cell surface receptor. Fluorescently labeled PMT-DTa and PMT colocalized with specific markers of early and late endosomes. Bafilomycin A, which inhibits vacuolar H ؉ -ATPase, blocked PMT-DTainduced intoxication of HEK-293 cells. By constructing various PMT-DTa chimeras, we identified a minimal region of PMT necessary for uptake of DTa. The data suggest that PMT is able to transport cargo proteins into eukaryotic cells by utilizing the PMT-specific uptake route.

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“…After binding, the toxin is internalized by both clathrin-dependent or independent endocytosis pathways, and is subsequently transferred to an endosomal compartment by a microtubule dependent mechanism [26]. At this level, conformational changes resulting from the acidification of late endosomes drive the translocation of the enzymatic domain into the cytoplasm [23] where CNF1 is cleaved in an approximately 55-kDa fragment that is necessary for full biological activity of the toxin [27]. …”

Section: The Cnf1 Protein: Structure and Activitymentioning

confidence: 99%

The Cytotoxic Necrotizing Factor 1 from E. Coli: A Janus Toxin Playing with Cancer Regulators

Fabbri

Travaglione

Ballan

et al. 2013

Toxins

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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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Cleavage of Escherichia coli Cytotoxic Necrotizing Factor 1 Is Required for Full Biologic Activity

Cited by 41 publications

References 19 publications

The Apoptogenic Toxin AIP56 Is a Metalloprotease A-B Toxin that Cleaves NF-κb P65

The Apoptogenic Toxin AIP56 Is a Metalloprotease A-B Toxin that Cleaves NF-κb P65

Pasteurella multocida Toxin as a Transporter of Non-Cell-Permeating Proteins

The Cytotoxic Necrotizing Factor 1 from E. Coli: A Janus Toxin Playing with Cancer Regulators

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