Receptors of anthrax toxin and cell entry

Goot, F. Gisou van der; Young, John A. T.

doi:10.1016/j.mam.2009.08.007

Cited by 77 publications

(105 citation statements)

References 60 publications

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“…The anthrax toxin, one of the two major virulence factors of Bacillus anthracis (5), is composed of three subunits, two of which are enzymes (6,7). Edema factor (EF) is a calmodulindependent adenylate cyclase, whereas lethal factor (LF) is a zincdependent metalloprotease that cleaves MAP kinase kinases (8,9).…”

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confidence: 99%

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confidence: 99%

“…It is produced by the bacterium as an 83-kDa form but requires processing to a 63-kDa form (PA63) either by plasma (12)(13)(14) or cellular proteases (7). PA63 has the ability to oligomerize into heptameric (PA 7mer ) (15) or octameric (16) rings that act as the receptors for EF and LF (7). The hetero-oligomeric complex is then internalized preferentially via a clathrin-mediated pathway (17) although other routes may be taken (18), possibly depending on the cell type and/or the ligand doses (19).…”

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confidence: 99%

“…Two receptors have been identified for the anthrax toxins: tumor endothelial marker 8 (TEM8) (20) and capillary morphogenesis gene 2 (CMG2) (7,21). Both are type I membrane proteins, bearing an extracellular von Willebrand factor domain involved in PA binding.…”

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confidence: 99%

“…Both are type I membrane proteins, bearing an extracellular von Willebrand factor domain involved in PA binding. TEM8 and CMG2 share a high degree of similarity in both their extracellular and cytoplasmic domains (7).…”

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confidence: 99%

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Anthrax toxin triggers the activation of src -like kinases to mediate its own uptake

Abrami

Kunz

Goot

2010

Proc. Natl. Acad. Sci. U.S.A.

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AB-type toxins, like other bacterial toxins, are notably opportunistic molecules. They rely on target cell receptors to reach the appropriate location within the target cell where translocation of their enzymatic subunits occurs. The anthrax toxin, however, times its own uptake, suggesting that toxin binding triggers specific signaling events. Here we show that the anthrax toxin triggers tyrosine phosphorylation of its own receptors, capillary morphogenesis gene 2 and tumor endothelial marker 8, which are not endowed with intrinsic kinase activity. This is required for efficient toxin uptake because endocytosis of the mutant receptor lacking the cytoplasmic tyrosine residues is strongly delayed. Phosphorylation of the receptors was dependent on src-like kinases, which where activated upon toxin binding. Importantly, src-dependent phosphorylation of the receptor was required for its subsequent ubiquitination, which in turn was required for clathrin-mediated endocytosis. Consistently, we found that uptake of the anthrax toxin and processing of the lethal factor substrate MEK1 are inhibited by silencing of src and fyn, as well as in src and fyn knockout cells.

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confidence: 99%

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confidence: 99%

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confidence: 99%

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confidence: 99%

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confidence: 99%

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Anthrax toxin triggers the activation of src -like kinases to mediate its own uptake

Abrami

Kunz

Goot

2010

Proc. Natl. Acad. Sci. U.S.A.

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Effect of endosomal acidification on small ion transport through the anthrax toxin PA₆₃ channel

et al. 2017

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Tight regulation of pH is critical for the structure and function of cells and organelles. The pH environment changes dramatically along the endocytic pathway, an internalization transport process that is 'hijacked' by many intracellularly active bacterial exotoxins, including the anthrax toxin. Here we investigate the role of pH on singlechannel properties of the anthrax toxin channel, PA 63 . Using conductance and current noise analysis, blocker binding, ion selectivity, and PEG partitioning measurements, we show that the channel exists in two different open states ('maximum' and 'main') at pH  5.5, while only a maximum conductance state is detected at pH  5.5. We describe two substantially distinct patterns of PA 63 conductance dependence on KCl concentration uncovered at pH 6.5 and 4.5.

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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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Receptors of anthrax toxin and cell entry

Cited by 77 publications

References 60 publications

Anthrax toxin triggers the activation of src -like kinases to mediate its own uptake

Anthrax toxin triggers the activation of src -like kinases to mediate its own uptake

Effect of endosomal acidification on small ion transport through the anthrax toxin PA₆₃ channel

Therapien gegen Bakterientoxine

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Receptors of anthrax toxin and cell entry

Cited by 77 publications

References 60 publications

Anthrax toxin triggers the activation of src -like kinases to mediate its own uptake

Anthrax toxin triggers the activation of src -like kinases to mediate its own uptake

Effect of endosomal acidification on small ion transport through the anthrax toxin PA63 channel

Therapien gegen Bakterientoxine

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Effect of endosomal acidification on small ion transport through the anthrax toxin PA₆₃ channel