Similarities in the action of different toxins

Heyningen, Simon van

doi:10.1016/b978-0-444-80400-6.50011-3

Cited by 11 publications

(6 citation statements)

References 106 publications

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“…Like cholera toxin, diphtheria toxin and the plant toxins abrin, ricin and modeccin are composed of two functionally active parts: a B moiety that binds to sites at the cell surface and an A moiety that has enzymatic properties and enters the cytosol [48]. Furthermore, evidence has been presented that these toxins are internalized into cells by adsorptive endocytosis.…”

Section: Discussionmentioning

confidence: 99%

Fate of injected ¹²⁵I‐labeled cholera toxin taken up by rat liver in vivo

Janicot

Desbuquois

1987

European Journal of Biochemistry

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Subcellular fractionation techniques have been used to assess the localization of injected 251-labeled cholera toxin (1251-CT) taken up by rat liver in vivo, and to determine whether internalization of the toxin is required for the generation of the active Al peptide.The uptake of injected 1251-CT into the liver is maximal at 5 min (about 10% injected dose/g). At this time the radioactivity is for the most part recovered in the microsomal (P) fraction, but later on it progressively associates with the mitochondrial-lysosomal (ML) and supernatant fractions. The radioactivity is enriched 7-fold in plasma membranes at 5 -15 min, and 15 -60-fold in Golgi-endosome (GE) fractions at 15 -60 min.On analytical sucrose gradients the radioactivity associated with the P fraction is progressively displaced from the region of 5'-nucleotidase (a plasma membrane marker) to that of galactosyltransferase (a Golgi marker). On Percoll gradients, however, it is displaced towards acid phosphatase (a lysosomal marker). Density-shift experiments, using Triton WR 1339, suggest that some radioactivity associated with the P fraction (at 30 min) and all the radioactivity present in the ML fraction (at 2 h) is intrinsic to acid-phosphatase-containing structures, presumably lysosomes. Comparable experiments using 3,3'-diaminobenzidine cytochemistry indicate that the radioactivity present in GE fractions is separable from galactosyltransferase, and thus is presumably associated with endosomes.The fate of injected 1251-labeled cholera toxin B subunit differs from that of the whole toxin by a more rapid uptake (and/or clearance) of the ligand into subcellular fractions, and a greater accumulation of ligand in the ML fraction.Analysis of GE fractions by SDS/polyacrylamide gel electrophoresis shows that, up to 10 min after injection of 1251-CT, about 80% of the radioactivity is recovered as A subunit and 20% as B subunit, similarly to control toxin. Later on there is a time-dependent decrease in the amount of A subunit and, at least with the intermediate GE fraction, a concomitant appearance of Al peptide (about 15% of the total at 60min). In contrast the radioactivity associated with plasma membranes remains indistinguishable from unused toxin.It is concluded that, upon interaction with hepatocytes, 1251-CT (both subunits A and B) sequentially associates with plasma membranes, endosomes and lysosomes, and that endosomes may represent the major subcellular site at which the Al peptide is generated.Cholera toxin (CT), a bacterial toxin which consists of two different non-covalently linked subunits, A and B [l -41, is known to exert its effects on cells by activation of adenylate cyclase [5, 61. The initial step in toxin action is the binding of its B subunit, composed of five identical peptides, to a specific cell-surface receptor, the ganglioside GM1 [7]. Subsequently the A subunit, which consists of two peptides linked by a single disulfide bond, Al and A2, is reduced, and the free Al peptide catalyses the activation of adenylate cyclase thro...

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Section: Discussionmentioning

confidence: 99%

Fate of injected ¹²⁵I‐labeled cholera toxin taken up by rat liver in vivo

Janicot

Desbuquois

1987

European Journal of Biochemistry

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“…When the disulfide bond is reduced, the heavy (Mr ,o100,000) and light (Mr ,050,000) chains can be separated using denaturing agents (e.g., urea or guanidine) (23). Several bacterial (e.g., cholera, diphtheria, and tetanus toxins) and plant (abrin and ricin) toxins as well as some glycoprotein hormones, which appear to act intraceUularly, also consist of two heterologous components (30,53). They seem to have a common strategy of access to their targets; one of the polypeptides binds to an acceptor on the external surface of the cell, while the other expresses its biological activity intracellularly.…”

mentioning

confidence: 99%

Interaction of 125I-labeled botulinum neurotoxins with nerve terminals. II. Autoradiographic evidence for its uptake into motor nerves by acceptor-mediated endocytosis.

Black¹,

Dolly²

1986

The Journal of Cell Biology

235

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Abstract. Using pharmacological (Simpson, L. L., 1980, J. Pharmacol. Exp. Ther. 212:16-21) and autoradiographic techniques (Black, J. D., and J. O. Dolly, 1986, J. Cell Biol., 103:521-534), it has been shown that botulinum neurotoxin (BoNT) is translocated across the motor nerve terminal membrane to reach a postulated intraterminal target. In the present study, the nature of this uptake process was investigated using electron microscopic autoradiography. It was found that internalization is acceptor-mediated and that binding to specific cell surface acceptors involves the heavier chain of the toxin. In addition, uptake was shown to be energy and temperature-dependent and to be accelerated by nerve stimulation, a treatment which also shortens the time course of the toxin-induced neuroparalysis. These results, together with the observation that silver grains were often associated with endocytic structures within the nerve terminal, suggested that acceptor-mediated endocytosis is responsible for toxin uptake. This proposal is supported further by the fact that lysosomotropic agents, which are known to interfere with the endocytic pathway, retard the onset of BoNT-induced neuroparalysis and also affect the distribution of silver grains at nerve terminals treated with L~5I-BoNT. Possible recycling of BoNT acceptors (an important aspect of acceptor-mediated endocytosis of toxins) at motor nerve terminals was indicated by comparing the extent of labeling in the presence and absence of metabolic inhibitors. On the basis of these collective results, it is concluded that BoNT is internalized by acceptor-mediated endocytosis and, hence, the data support the proposal that this toxin inhibits release of acetylcholine by interaction with an intracellular target.

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“…The H and L fragments are formed by proteolytic nicking of the native polypeptide chain and can be separated after reduction of disulphide bonds. This type of structure suggests an analogy with known bipartite toxin (van Heyningen 1982). If this model is correct, then binding of the H fragment probably results in penetration by the L region of the membrane of the inhibitory motor neuron at the inhibitory synapse.…”

Section: Tetanus Toxinmentioning

confidence: 78%

“…In some instances detailed-information is available on the role of enterotoxins in pathogenesis and on the mode of toxin action. Cholera enterotoxin and the LT and ST enterotoxins of E. coli are examples of well characterized enterotoxins (for reviews see van Heyningen (1982), Johnson (1982) and Greenberg & Guerrant (1981)).…”

Section: T Oxin Action On Mucosal Epithelial Surfacesmentioning

confidence: 99%

Host damage from bacterial toxins

Arbuthnott

Rutter²,

Glynn³

1983

Phil. Trans. R. Soc. Lond. B

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Bacterial infection often involves toxin-mediated damage to the host. This can occur at mucosal epithelial surfaces, in subepithelial tissues (involving connective tissue, blood vessels and host defence cells), or at organ or tissue sites distant from the focus of infection. This paper deals with host damage at each of these levels and examples have been selected of toxins that have a well defined role in pathogenesis and for which evidence is less clear cut. Current views of mechanisms of host damage are presented along with summaries of mode of action at the molecular level where this is known. Certain unifying features of mechanisms of toxin action on host cells are emphasised. Modern genetic methods and gene cloning techniques should help in the assessment of the role of individual toxic factors where pathogenesis is multifactorial, and preliminary examples of this approach are mentioned. The search for new toxins continues and this is illustrated with reference to the toxins involved in the staphylococcal scalded skin syndrome and staphylococcal toxic shock syndrome. This overview is intended to convey an impression of the rapid development that has taken place in knowledge of the role of toxins in pathogenesis.

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Similarities in the action of different toxins

Cited by 11 publications

References 106 publications

Fate of injected ¹²⁵I‐labeled cholera toxin taken up by rat liver in vivo

Fate of injected ¹²⁵I‐labeled cholera toxin taken up by rat liver in vivo

Interaction of 125I-labeled botulinum neurotoxins with nerve terminals. II. Autoradiographic evidence for its uptake into motor nerves by acceptor-mediated endocytosis.

Host damage from bacterial toxins

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Similarities in the action of different toxins

Cited by 11 publications

References 106 publications

Fate of injected 125I‐labeled cholera toxin taken up by rat liver in vivo

Fate of injected 125I‐labeled cholera toxin taken up by rat liver in vivo

Interaction of 125I-labeled botulinum neurotoxins with nerve terminals. II. Autoradiographic evidence for its uptake into motor nerves by acceptor-mediated endocytosis.

Host damage from bacterial toxins

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Fate of injected ¹²⁵I‐labeled cholera toxin taken up by rat liver in vivo

Fate of injected ¹²⁵I‐labeled cholera toxin taken up by rat liver in vivo