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Toxins 2017, 9(1), 2; doi:10.3390/toxins9010002

Role of p38alpha/beta MAP Kinase in Cell Susceptibility to Clostridium sordellii Lethal Toxin and Clostridium difficile Toxin B

Institute for Toxicology, Hannover Medical School, Carl-Neuberg-Str. 1, D-30625 Hannover, Germany
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Author to whom correspondence should be addressed.
Academic Editor: Holger Barth
Received: 12 September 2016 / Revised: 16 December 2016 / Accepted: 19 December 2016 / Published: 22 December 2016
(This article belongs to the Special Issue Novel Pharmacological Inhibitors for Bacterial Protein Toxins)
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Abstract

Lethal Toxin from Clostridium 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 p38alpha expression (p38alpha−/− MSCV p38alpha MEFs). Genetic deletion of p38alpha results in reduced susceptibility of cells to TcsL-induced Rac/Cdc42 glucosylation and actin reorganization. Furthermore, SB203580, a pyridinyl imidazole inhibitor of p38alpha/beta MAP kinase, also protects cells from TcsL-induced effects in both p38−/− MSCV empty vector MEFs and in p38alpha−/− MSCV p38alpha MEFs, suggesting that inhibition of p38beta contributes to the protective effect of SB203580. In contrast, the effects of the related C. difficile Toxin B are responsive neither to SB203580 treatment nor to p38alpha deletion. In conclusion, the protective effects of SB203580 and of p38alpha deletion are likely not based on inhibition of the toxins’ glucosyltransferase activity rather than on inhibited endocytic uptake of specifically TcsL into target cells. View Full-Text
Keywords: endocytosis; Ras; C. difficile Toxin B; mono-O-glucosylation; p21-activated kinase; actin endocytosis; Ras; C. difficile Toxin B; mono-O-glucosylation; p21-activated kinase; actin
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MDPI and ACS Style

Schelle, I.; Bruening, J.; Buetepage, M.; Genth, H. Role of p38alpha/beta MAP Kinase in Cell Susceptibility to Clostridium sordellii Lethal Toxin and Clostridium difficile Toxin B. Toxins 2017, 9, 2.

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