title: Role of p38alpha/betaMAP Kinase in Cell Susceptibility to Clostridium sordellii Lethal Toxin and Clostridium difficile Toxin B.
abstract: Lethal Toxin fromClostridium sordellii(TcsL), which is casually involved in the toxic shock syndrome and in gas gangrene, enters its target cells by receptor-mediated endocytosis. Inside the cell, TcsL mono-O-glucosylates and thereby inactivates Rac/Cdc42 and Ras subtype GTPases, resulting in actin reorganization and an activation of p38 MAP kinase. While a role of p38 MAP kinase in TcsL-induced cell death is well established, data on a role of p38 MAP kinase in TcsL-induced actin reorganization are not available. In this study, TcsL-induced Rac/Cdc42 glucosylation and actin reorganization are differentially analyzed in p38alpha-/-MSCV empty vector MEFs and the corresponding cell line with reconstituted p38alphaexpression (p38alpha-/-MSCV p38alphaMEFs). Genetic deletion of p38alpharesults in reduced susceptibility of cells to TcsL-induced Rac/Cdc42 glucosylation and actin reorganization. Furthermore, SB203580, a pyridinyl imidazole inhibitor of p38alpha/betaMAP kinase, also protects cells from TcsL-induced effects in both p38-/-MSCV empty vector MEFs and in p38alpha-/-MSCV p38alphaMEFs, suggesting that inhibition of p38betacontributes to the protective effect of SB203580. In contrast, the effects of the relatedC. difficileToxin B are responsive neither to SB203580 treatment nor to p38alphadeletion. In conclusion, the protective effects of SB203580 and of p38alphadeletion are likely not based on inhibition of the toxins' glucosyltransferase activity rather than on inhibited endocytic uptake of specifically TcsL into target cells.
authors.affiliation: Institute for Toxicology, Hannover Medical School, Carl-Neuberg-Str. 1, D-30625 Hannover, Germany. ilona.schelle@t-online.de.
authors.forename: Ilona
authors.initials: I
authors.lastname: Schelle
authors.affiliation: Institute for Toxicology, Hannover Medical School, Carl-Neuberg-Str. 1, D-30625 Hannover, Germany. janina.bruening@twincore.de.
authors.forename: Janina
authors.initials: J
authors.lastname: Bruening
authors.affiliation: Institute for Toxicology, Hannover Medical School, Carl-Neuberg-Str. 1, D-30625 Hannover, Germany. mbuetepage@ukaachen.de.
authors.forename: Mareike
authors.initials: M
authors.lastname: Buetepage
authors.affiliation: Institute for Toxicology, Hannover Medical School, Carl-Neuberg-Str. 1, D-30625 Hannover, Germany. genth.harald@mh-hannover.de.
authors.forename: Harald
authors.initials: H
authors.lastname: Genth
mesh_terms: D000818:Animals; D001426:Bacterial Proteins / Q000633:toxicity*; D001427:Bacterial Toxins / Q000633:toxicity*; D002460:Cell Line; D016360:Clostridioides difficile; D047989:Paraclostridium sordellii; D004285:Dogs; D005347:Fibroblasts / Q000187:drug effects / Q000378:metabolism; D017353:Gene Deletion; D007093:Imidazoles / Q000494:pharmacology; D061985:Madin Darby Canine Kidney Cells; D051379:Mice; D048290:Mitogen-Activated Protein Kinase 11 / Q000037:antagonists & inhibitors / Q000235:genetics* / Q000378:metabolism; D048308:Mitogen-Activated Protein Kinase 14 / Q000037:antagonists & inhibitors / Q000235:genetics* / Q000378:metabolism; D011725:Pyridines / Q000494:pharmacology
chemical_list: D001426:Bacterial Proteins; D001427:Bacterial Toxins; D007093:Imidazoles; D011725:Pyridines; C072292:lethal toxin LT, Clostridium sordellii; C031815:toxB protein, Clostridium difficile; C029899:imidazole; D048290:Mitogen-Activated Protein Kinase 11; D048308:Mitogen-Activated Protein Kinase 14; C093642:SB 203580
keywords: C. difficile Toxin B; Ras; actin; endocytosis; mono-O-glucosylation; p21-activated kinase