PMID- 28025502
OWN - NLM
STAT- MEDLINE
DCOM- 20171211
LR  - 20201209
IS  - 2072-6651 (Electronic)
IS  - 2072-6651 (Linking)
VI  - 9
IP  - 1
DP  - 2016 Dec 22
TI  - Role of p38(alpha/beta) MAP Kinase in Cell Susceptibility to Clostridium 
      sordellii Lethal Toxin and Clostridium difficile Toxin B.
LID - 10.3390/toxins9010002 [doi]
LID - 2
AB  - 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.
FAU - Schelle, Ilona
AU  - Schelle I
AD  - Institute for Toxicology, Hannover Medical School, Carl-Neuberg-Str. 1, D-30625 
      Hannover, Germany. ilona.schelle@t-online.de.
FAU - Bruening, Janina
AU  - Bruening J
AD  - Institute for Toxicology, Hannover Medical School, Carl-Neuberg-Str. 1, D-30625 
      Hannover, Germany. janina.bruening@twincore.de.
FAU - Buetepage, Mareike
AU  - Buetepage M
AD  - Institute for Toxicology, Hannover Medical School, Carl-Neuberg-Str. 1, D-30625 
      Hannover, Germany. mbuetepage@ukaachen.de.
FAU - Genth, Harald
AU  - Genth H
AD  - Institute for Toxicology, Hannover Medical School, Carl-Neuberg-Str. 1, D-30625 
      Hannover, Germany. genth.harald@mh-hannover.de.
LA  - eng
PT  - Journal Article
DEP - 20161222
PL  - Switzerland
TA  - Toxins (Basel)
JT  - Toxins
JID - 101530765
RN  - 0 (Bacterial Proteins)
RN  - 0 (Bacterial Toxins)
RN  - 0 (Imidazoles)
RN  - 0 (Pyridines)
RN  - 0 (lethal toxin LT, Clostridium sordellii)
RN  - 0 (toxB protein, Clostridium difficile)
RN  - 7GBN705NH1 (imidazole)
RN  - EC 2.7.11.24 (Mitogen-Activated Protein Kinase 11)
RN  - EC 2.7.11.24 (Mitogen-Activated Protein Kinase 14)
RN  - OU13V1EYWQ (SB 203580)
SB  - IM
MH  - Animals
MH  - Bacterial Proteins/*toxicity
MH  - Bacterial Toxins/*toxicity
MH  - Cell Line
MH  - Clostridioides difficile
MH  - Clostridium sordellii
MH  - Dogs
MH  - Fibroblasts/drug effects/metabolism
MH  - Gene Deletion
MH  - Imidazoles/pharmacology
MH  - Madin Darby Canine Kidney Cells
MH  - Mice
MH  - Mitogen-Activated Protein Kinase 11/antagonists & inhibitors/*genetics/metabolism
MH  - Mitogen-Activated Protein Kinase 14/antagonists & inhibitors/*genetics/metabolism
MH  - Pyridines/pharmacology
PMC - PMC5308236
OTO - NOTNLM
OT  - C. difficile Toxin B
OT  - Ras
OT  - actin
OT  - endocytosis
OT  - mono-O-glucosylation
OT  - p21-activated kinase
COIS- The authors declare no conflict of interest. The founding sponsors had no role in 
      the design of the study; in the collection, analyses, or interpretation of data; 
      in the writing of the manuscript, and in the decision to publish the results.
EDAT- 2016/12/28 06:00
MHDA- 2017/12/12 06:00
PMCR- 2017/01/01
CRDT- 2016/12/28 06:00
PHST- 2016/09/12 00:00 [received]
PHST- 2016/12/16 00:00 [revised]
PHST- 2016/12/19 00:00 [accepted]
PHST- 2016/12/28 06:00 [entrez]
PHST- 2016/12/28 06:00 [pubmed]
PHST- 2017/12/12 06:00 [medline]
PHST- 2017/01/01 00:00 [pmc-release]
AID - toxins9010002 [pii]
AID - toxins-09-00002 [pii]
AID - 10.3390/toxins9010002 [doi]
PST - epublish
SO  - Toxins (Basel). 2016 Dec 22;9(1):2. doi: 10.3390/toxins9010002.