Pore-forming toxins activate MAPK p38 by causing loss of cellular potassium.
Mitogen activated protein kinase (MAPK) p38 has emerged as a survival protein in cells that are attacked by bacterial toxins forming small membrane pores. Activation of p38 by pore forming toxins (PFT) has been attributed to osmotic stress, but here we show that loss of K+ is likely to be the critical parameter. Several lines of evidence support this conclusion: first, osmoprotection did not prevent p38-phosphorylation in alpha-toxin-loaded cells. Second, treatment of cells with a K+ ionophore, or simple incubation in K+-free medium sufficed to cause robust p38-phosphorylation. Third, media containing high [K+] prevented p38-activation by Staphylococcus aureus alpha-toxin, Vibrio cholerae cytolysin (VCC), Streptolysin O (SLO), or Escherichia coli hemolysin (HlyA), but did not impair activation by H2O2. Fourth, potential roles of LPS, TLR4, or calcium-influx were ruled out. Therefore, we propose that PFT trigger the p38 MAPK-pathway by causing loss of cellular K+.
Kloft
Nicole
N
Institut für Medizinische Mikrobiologie und Hygiene, Universitätsmedizin, Johannes Gutenberg-Universität, Mainz, Germany.
Busch
Tim
T
Neukirch
Claudia
C
Weis
Silvia
S
Boukhallouk
Fatima
F
Bobkiewicz
Wiesia
W
Cibis
Ingo
I
Bhakdi
Sucharit
S
Husmann
Matthias
M
D001427:Bacterial Toxins / Q000633:toxicity*; D002118:Calcium / Q000378:metabolism; D002460:Cell Line; D002462:Cell Membrane / Q000187:drug effects* / Q000201:enzymology; D004789:Enzyme Activation; D004847:Epithelial Cells / Q000187:drug effects* / Q000201:enzymology; D029968:Escherichia coli Proteins / Q000633:toxicity; D006460:Hemolysin Proteins / Q000633:toxicity; D006801:Humans; D010766:Phosphorylation; D052899:Pore Forming Cytotoxic Proteins / Q000633:toxicity*; D011188:Potassium / Q000378:metabolism*; D048051:p38 Mitogen-Activated Protein Kinases / Q000096:biosynthesis*
D001427:Bacterial Toxins; D029968:Escherichia coli Proteins; D006460:Hemolysin Proteins; C036507:Hlya protein, E coli; D052899:Pore Forming Cytotoxic Proteins; D048051:p38 Mitogen-Activated Protein Kinases; D011188:Potassium; D002118:Calcium