Molecular, functional, and evolutionary aspects of ADP-ribosylating toxins

Masignani, Vega; Pizza, Mariagrazia; Rappuoli, Rino

doi:10.1016/b978-012088445-2/50017-2

Cited by 11 publications

(11 citation statements)

References 243 publications

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“…aexT is a bifunctional protein with ADP-ribosylating activity and guanosine triphosphatase-activating protein (GAP) activity (Fehr et al 2007). aexT mediates ADP-ribosylation of both muscular and non-muscular actin in vitro (Fehr et al 2007), thereby preventing polymerization (Masignani et al 2006 (Fehr et al 2007, Vilches et al 2008. ascV is a gene that serves as an indicator for the presence of the TTSS machinery (Stuber et al 2003), which encodes an inner membrane component of the TTSS apparatus, and ascF-ascG encode the needle complex and a chaperone, respectively (Ghosh 2004).…”

Section: Discussionmentioning

confidence: 99%

Isolation and characterization of virulent Aeromonas veronii from ascitic fluid of oscar Astronotus ocellatus showing signs of infectious dropsy

Sreedharan¹,

Philip²,

Singh³

2011

Dis. Aquat. Org.

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The cichlid oscar Astronotus ocellatus has worldwide commercial value in the pet fish industry because of its early maturation, relatively high fecundity, ability to identify its caretaker and also to alter colouration amongst conspecifics. Pathogenic strains of Aeromonas veronii resistant to multiple antibiotics were isolated from A. ocellatus individuals showing signs of infectious abdominal dropsy. The moribund fish showed haemorrhage in all internal organs, and pure cultures could be obtained from the abdominal fluid. The isolates recovered were biochemically identified as A. veronii biovar sobria and genetically confirmed as A. veronii based on 16S rRNA gene sequence analysis (GenBank accession no. FJ573179). The RAPD profile using 3 primers (OPA-3, OPA-4 and OPD-20) generated similar banding patterns for all isolates. They displayed cytotoxic and haemolytic activity and produced several exoenzymes which were responsible for the pathogenic potential of the isolates. In the representative isolate MCCB 137, virulence genes such as enterotoxin act, haemolytic toxin aerA, type 3 secretion genes such as aexT, ascV and ascF-ascG, and gcat (glycerophospholipidcholesterol acyltransferase) could be amplified. MCCB 137 exhibited a 50% lethal dose (LD 50 ) of 10 5.071 colony-forming units ml -1 in goldfish and could be subsequently recovered from lesions as well as from the internal organs. This is the first description of a virulent A. veronii from oscar. KEY WORDS: Aeromonas veronii · Oscar · Astronotus ocellatus · Virulence · Ornamental fishesResale or republication not permitted without written consent of the publisher

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Section: Discussionmentioning

confidence: 99%

Isolation and characterization of virulent Aeromonas veronii from ascitic fluid of oscar Astronotus ocellatus showing signs of infectious dropsy

Sreedharan¹,

Philip²,

Singh³

2011

Dis. Aquat. Org.

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“…It is interesting to note that these residues are separated by two amino acids, instead of only one as in other ADP-ribosylating toxins possessing a biglutamic motif (Fig. 3A) (27).…”

Section: Resultsmentioning

confidence: 99%

“…The cholera toxin group of ADP-ribosylating toxins, which includes iota toxin and other ADP-ribosylating toxins that target actin, contains a conserved arginine residue that is required to maintain the stability of the active site pocket. In the diphtheria toxin group, a histidine residue rather than an arginine carries out this function (27). Sequence alignment of AexT with cholera toxin suggests that Arg-303 or Arg-306 in AexT could be the conserved, functional arginine residue of the cholera toxin group (Fig.…”

Section: Resultsmentioning

confidence: 99%

“…This region accommodates a molecule of NAD and possesses a catalytic glutamic acid residue essential for the enzymatic activity (27). The active site of certain toxins, including actin-ADP-ribosylating toxins such as iota toxin, contain not one but two glutamic acid residues whereby both residues are required for the ADP-ribosylation activity (27,28).…”

Section: Resultsmentioning

confidence: 99%

“…This residue is located at the contact site between actin monomers. ADP-ribosylation of monomeric actin prevents contact with other actin monomers thereby preventing polymerization (27). Arg-177 has also been shown to the modification site of SpvB and C2 toxin as well as of iota toxin (26,38,39).…”

Section: Discussionmentioning

confidence: 99%

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Aeromonas Exoenzyme T of Aeromonas salmonicida Is a Bifunctional Protein That Targets the Host Cytoskeleton

Fehr

Burr

Gibert

et al. 2007

Journal of Biological Chemistry

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Type III protein secretion has been shown recently to be important in the virulence of the fish pathogen Aeromonas salmonicida. The ADP-ribosylating toxin Aeromonas exoenzyme T (AexT) is one effector protein targeted for secretion via this system. In this study, we identified muscular and nonmuscular actin as substrates of the ADP-ribosylating activity of AexT. Furthermore, we show that AexT also functions as a GTPaseactivating protein (GAP), displaying GAP activity against monomeric GTPases of the Rho family, specifically Rho, Rac, and Cdc42. Transfection of fish cells with wild type AexT resulted in depolymerization of the actin cytoskeleton and cell rounding. Point mutations within either the GAP or the ADP-ribosylating active sites of AexT (Arg-143 as well as Glu-398 and Glu-401, respectively) abolished enzymatic activity, yet did not prevent actin filament depolymerization. However, inactivation of the two catalytic sites simultaneously did. These results suggest that both the GAP and ADP-ribosylating domains of AexT contribute to its biological activity. This is the first bacterial virulence factor to be described that has a specific actin ADP-ribosylation activity and GAP activity toward Rho, Rac, and Cdc42, both enzymatic activities contributing to actin filament depolymerization.Aeromonas salmonicida subsp. salmonicida (A. salmonicida) is the causative agent of furunculosis, a systemic disease that affects salmonid fish (salmon, trout, and char). A. salmonicida expresses a variety of extracellular toxins, many of which have been implicated in virulence. Several of these factors, including the pore-forming toxin aerolysin, serine protease, and the phospholipase GCAT, are secreted into the environment via the well characterized type II or general secretory pathway (1, 2). However, like many Gram-negative pathogens, A. salmonicida also possesses a type III protein secretion system (3-5). Such secretion systems translocate toxins, or type III effector proteins, directly into the cytosol of eukaryotic cells. Here the effector proteins are able to modulate cell signaling pathways or, alternatively, disrupt the dynamics of the cytoskeleton (6, 7).To date, the following genes encoding four type III effector proteins have been identified in A. salmonicida: aexT, aopP, aopO, and aopH (8 -10). Although functional studies of AopO and AopH have not yet been carried out, sequence homology with type III effector proteins YopO and YopH of Yersinia sp. suggests that AopO and AopH modify the actin cytoskeleton of target eukaryotic cells. In contrast, AopP has been shown to interfere with the NF-B signaling pathway by inhibiting translocation of NF-B into the nucleus of target cells (10).AexT, the first type III effector of A. salmonicida to be characterized, has been shown to function as an ADP-ribosylating toxin (8). However, its substrate has never before been identified. AexT also displays significant sequence homology to the bifunctional type III effector proteins ExoS and ExoT, expressed by Pseudomonas aeruginosa. ...

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Therapien gegen Bakterientoxine

2012

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Proteintoxine sind die hauptsächlichen Virulenzfaktoren einiger Bakterienarten und haben sich in der Wirkstoff‐Entwicklung als vielversprechende Zielstrukturen erwiesen. Leitsubstanzen, die auf Bakterientoxine abzielen, variieren von niedermolekularen Verbindungen zu polymeren Bindungsstoffen, und sie greifen beim Mechanismus der Toxin‐vermittelten Pathogenität in jeden der vielen Schritte ein. Auch wenn in diesem Bereich in letzter Zeit bedeutende Fortschritte erzielt wurden, hat es bisher noch kein rational entwickelter Wirkstoff gegen Toxine zur Marktreife gebracht. Dieser Aufsatz bietet einen Überblick über den Stand der Forschung bei der Entwicklung von Wirkstoffen gegen Bakterientoxine, mit kritischer Beleuchtung der erzielten Durchbrüche wie auch der noch zu nehmenden Hürden. Die Diskussion konzentriert sich auf Proteintoxine vom A‐B‐Typ, die von vier Bakterienarten sezerniert werden, nämlich Clostridium difficile (Toxine A und B), Vibrio cholerae (Cholera‐Toxin), enterohämorrhagische Escherichia coli (Shiga‐Toxin) und Bacillus anthracis (Anthrax‐Toxin). Dies sind die Krankheitserreger, für die Therapien zu verbessern sind.

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Molecular, functional, and evolutionary aspects of ADP-ribosylating toxins

Cited by 11 publications

References 243 publications

Isolation and characterization of virulent Aeromonas veronii from ascitic fluid of oscar Astronotus ocellatus showing signs of infectious dropsy

Isolation and characterization of virulent Aeromonas veronii from ascitic fluid of oscar Astronotus ocellatus showing signs of infectious dropsy

Aeromonas Exoenzyme T of Aeromonas salmonicida Is a Bifunctional Protein That Targets the Host Cytoskeleton

Therapien gegen Bakterientoxine

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