Role of p38(alpha/beta) MAP Kinase in Cell Susceptibility to Clostridium sordellii Lethal Toxin and Clostridium difficile Toxin B

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 p38(alpha)(−/−) MSCV empty vector MEFs and the corresponding cell line with reconstituted p38(alpha) expression (p38(alpha)(−/−) MSCV p38(alpha) MEFs). Genetic deletion of p38(alpha) results in reduced susceptibility of cells to TcsL-induced Rac/Cdc42 glucosylation and actin reorganization. Furthermore, SB203580, a pyridinyl imidazole inhibitor of p38(alpha/beta) MAP kinase, also protects cells from TcsL-induced effects in both p38(−/−) MSCV empty vector MEFs and in p38(alpha)(−/−) MSCV p38(alpha) MEFs, suggesting that inhibition of p38(beta) 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 p38(alpha) deletion. In conclusion, the protective effects of SB203580 and of p38(alpha) deletion are likely not based on inhibition of the toxins’ glucosyltransferase activity rather than on inhibited endocytic uptake of specifically TcsL into target cells.