Signal transduction pathways and cellular intoxication with Clostridium difficile toxins.
In cultured cells the cytopathic effects (CPE) of Clostridium difficile toxins A and B are superficially similar. The irreversible CPEs involve a reorganization of the cytoskeleton, but the molecular details of the mechanism(s) of action are unknown. As part of the work to elucidate the events leading to the CPE, cultured cells were preincubated with agents known to either stimulate or inhibit some major signal transduction pathways, whereupon toxin was added and the development of the CPE was followed. Both toxin-induced CPEs were enhanced by phorbol esters and mezerein, which stimulate protein kinase C, while they were inhibited by the phospholipase A2 inhibitors quinacrine and 4-bromophenacylbromide. Agents affecting certain G-proteins, cGMP and cAMP levels, phosphatases, prostacyclin, lipoxygenase, and phospholipase C did not affect the development of the CPE of either toxin. Thus, the cytoskeletal effect induced by toxins A or B appears to require PLA2 activity and involves at least part of a protein kinase C-dependent pathway, but not pertussis toxin-sensitive G-proteins, cyclic nucleotides, eicosanoid metabolites, or phospholipase C activity. In addition, both toxins were shown to activate phospholipase A2.
Shoshan
M C
MC
Department of Bacteriology, Karolinska Institute, Stockholm, Sweden.
Fiorentini
C
C
Thelestam
M
M
D001426:Bacterial Proteins; D001427:Bacterial Toxins / Q000506:poisoning*; D002478:Cells, Cultured; D016360:Clostridioides difficile; D003603:Cytotoxins / Q000506:poisoning*; D004768:Enterotoxins / Q000506:poisoning*; D004789:Enzyme Activation / Q000187:drug effects; D019204:GTP-Binding Proteins / Q000187:drug effects; D006801:Humans; D009712:Nucleotides, Cyclic / Q000378:metabolism; D010716:Phosphatidylinositols / Q000378:metabolism; D010741:Phospholipases A / Q000187:drug effects; D054467:Phospholipases A2; D010766:Phosphorylation; D015398:Signal Transduction / Q000187:drug effects*; D010738:Type C Phospholipases / Q000187:drug effects
D001426:Bacterial Proteins; D001427:Bacterial Toxins; D003603:Cytotoxins; D004768:Enterotoxins; D009712:Nucleotides, Cyclic; D010716:Phosphatidylinositols; C041348:tcdA protein, Clostridium difficile; C031815:toxB protein, Clostridium difficile; D010741:Phospholipases A; D054467:Phospholipases A2; D010738:Type C Phospholipases; D019204:GTP-Binding Proteins