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metabolism
cytotoxin A possesses an inherent cysteine protease activity, which is responsible for auto-cleavage of glucosylating toxins
malfunction
the deletion mutant TcdBD1756-1780 shows similar glucosyltransferase and cysteine protease activity, cellular binding, and pore formation to wild-type TcdB, but it fails to induce the glucosylation of Rho GTPase Rac1 of host cells. Moreover, TcdBD1756-1780 is rapidly degraded in the endosome of target cells, and therefore its intact glucosyltransferase domain is unable to translocate efficiently into host cytosol. The decrease in the alpha helical structure in the composition of TcdBD1756-1780 may be due to the deletion of AA 1756-1780. Domain structures of wild-type and mutant enzymes, overview. The deletion of region 1756-1780 might lead to locking of the TcdB in endosomes, resulting in a failure to deliver GTD
metabolism
cytotoxin B possesses an inherent cysteine protease activity, which is responsible for auto-cleavage of glucosylating toxins
additional information
the toxin requires InsP6-dependent autocleavage for activation
physiological function
sub-lethal concentrations of Clostridium difficile TcdA are able to alter cell polarity by causing redistribution of plasma membrane components between distinct surface domains
physiological function
Clostridioides difficile toxin A (TcdA) and Toxin B (TcdB) trigger inflammasome activation with caspase-1 activation in cultured cells, which in turn induce the release of IL-6, IFN-g, and IL-8. Release of these proinflammatory responses is positively regulated by Ras-GTPases, which leads to the hypothesis that Ras glucosylation by glucosylating toxins results in (at least) reduced proinflammatory responses. Quantitative evaluation of the GTPase substrate profiles glucosylated in human colonic (Caco-2) cells treated with either TcdA, TcdB, or the related Clostridium sordellii lethal toxin (TcsL), performed by using multiple reaction monitoring (MRM) mass spectrometry. TcdA (not TcdB) glucosylates Ras subtype GTPases correlating with the fact that TcdB (not TcdA) is primarily responsible for inflammatory responses in Clostridioides difficile infection (CDI)
physiological function
-
in cell culture toxin A inhibits Clostridium botulinum ADP-ribosyltransferase C3-catalyzed ADP-ribosylation of the low molecular mass GTP-binding Rho proteins. Toxin A-induced decrease in ADP-ribosylation is observed also in cell lysates and with recombinant RhoA protein
physiological function
-
microinjection of RhoA previously glucosylated by toxin B into monolayer cells causes disaggregation of actin filaments, indicating a dominant-negative activity of glucosylated RhoA
physiological function
-
phosphorylated mitogen-activated protein kinase MK-2 is activated by toxins TcdA and TcdB and regulates the expression of proinflammatory cytokines. Activation of p38-MK2 in infected animals and humans suggests that this pathway is a key driver of intestinal inflammation in patients with Clostridium difficile infection
physiological function
-
stimulation of murine intestinal epithelial cells with toxin A results in the upregulation of chemokine CX3CL1. Expression of CX3CL1 is dependent on nuclear factor kappaB and I?appaB kinase activation. A pathway, including p38 mitogen-activated protein kinase, IkappaB kinase , and nuclear factor kappaB activation, is required for CX3CL1 induction in intestinal epithelial cells exposed to toxin A and may regulate the development of intestinal inflammation induced by infection with toxigenic Peptoclostridium difficile
physiological function
-
strain 8864 which does not produce toxin A produces a modified toxin B. After treatment of fibroblasts with toxin B from strain 10463, which produces both toxin A and toxin B, cells become rounded and highly arborised, giving the characteristic actinomorphic appearance. With the toxin B from strain 8864, no arborisation of cells occurrs but there is rounding and significant detachment
physiological function
-
toxin A interacts with ERK1 and ERK2 in human colonocyte cell lines NCM460 and HT29 by direct binding thereby inhibiting their kinase activites
physiological function
-
toxin A significantly decreases activating phosphorylations of erythropoietin receptor EpoR and its downstream signaling molecules Janus kinase JAK-2 and signal transducer and activator of transcription STAT5. Inhibition of JAK2 by toxin A in colonocytes causes inactivation of EpoR, thereby enhancing the inhibition of focal contact formation and loss of tight junctions known to be associated with the enzymatic activity of toxin A
physiological function
-
toxin A, toxin B or crude toxin preparations have no effect on membrane integrity of either intestinal cells or McCoy cells as judged by nucleotide leakage. Toxins A and B, on their own ortogether in crude preparations, have no effect on the rate of protein synthesis in isolated intestinal cells in vitro. Both toxins inhibit protein synthesis in McCoy cells, and inhibition of protein synthesis could be a causative factor in the development of cytopathic effects
physiological function
-
toxin A-positive, toxin B-positive strains representing 12 variant toxinotypes all express considerably lower levels of toxin A and are less cytotoxic in vitro than non-variant strain VPI 10463. Truncated forms of toxin occur in toxinotype VI and VII strains and these toxins are differentiated from each other and from toxin A of the non-variant strain. Toxin A-positive, toxin B-positive strains of toxinotypes IX, XIV and XV are able to exhibit an alternative Clostridium sordellii-like cytopathic effect on Vero cells, characterized by marked cell clumping. The abnormal cytotoxicity observed for these strains is due to an altered toxin B
physiological function
-
toxin B elicits an arachidonic acid release in a cell mutant resistant to the toxin B effect on the microfilaments. This effect effect is neither a cause nor a consequence of toxin-induced microfilament disorganization
physiological function
-
toxin B stimulates secretion from isolated pancreatic acini. Doses of toxin B from 10-30 ng/ml increases enzyme secretion by 15-20%, doses between 30 ng and 60 ng/ml show a regression of this effect, whereafter the rate of secretion of amylase, trypsinogen, and chymotrypsinogen increases with increasing concentrations of the toxin. Toxin B concentration of 800 ng/ml enhances amylase, trypsinogen and chymotrypsinogen secretion by 119%, 185% and 195%, respectively, when compared with the basal level
physiological function
quantitative evaluation of the GTPase substrate profiles glucosylated in human colonic (Caco-2) cells treated with either TcdA, TcdB, or the related Clostridium sordellii lethal toxin (TcsL), performed by using multiple reaction monitoring (MRM) mass spectrometry. TcdA (not TcdB) glucosylates Ras subtype GTPases correlating with the fact that TcdB (not TcdA) is primarily responsible for inflammatory responses in Clostridioides difficile
physiological function
two exotoxins, toxin A (TcdA) and toxin B (TcdB), are the major virulence factors involved in Clostridium difficile infection (CDI), and both belong to the family of clostridial glucosylating toxins. The toxins are multi-domain proteins containing at least four functional domains. The N-terminus of the toxin harbors the glucosyltransferase domain (GTD) that inactivates host Rho GTPases by glucosylation and a cysteine protease domain (CPD) responsible for autoprocessing. The C-terminus, consisting of combined repetitive oligopeptides (CROP), is predicted to be a receptor binding domain (RBD). The receptor for TcdB has been identified recently, but additional receptors may exist. A large region between the CPD and RBD is thought to be the translocation domain (TD) which is important for delivery of N-terminal enzymatic domains into the host cytosol via pore formation. The segment of 97 amino acids (AA 1756-1852, designated D97) within the translocation domain of TcdB is essential for the in vitro and in vivo toxicity of TcdB. smaller fragment, amino acids 1756-1780, located in the N-terminus of the D97 fragment, is essential for translocation of the effector glucosyltransferase domain into the host cytosol. A sequence of 25AA within D97 is predicted to form an alpha helical structure and is the critical part of D97
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