Listeria monocytogenes invasion of epithelial cells requires the MEK-1/ERK-2 mitogen-activated protein kinase pathway.
PD98059, a specific inhibitor of MEK-1 mitogen-activated protein (MAP) kinase kinase, blocked Listeria monocytogenes invasion into HeLa epithelial cells. The effects of PD98059 were reversible, as adherent extracellular bacteria were internalized upon removal of the drug. Previously, we reported that L. monocytogenes could activate ERK-1 and ERK-2 MAP kinases through the action of listeriolysin O (LLO) on the host cell (P. Tang, I. Rosenshine, P. Cossart, and B. B. Finlay, Infect. Immun. 64:2359-2361, 1996). We have now found that two other MAP kinase pathways, those of p38 MAP kinase and c-Jun N-terminal kinase, are also activated by wild-type L. monocytogenes. Mutants lacking functional LLO (hly mutants) were still invasive but only activated ERK-2 and only activated it at later (90-min) postinfection times. Two inhibitors of L. monocytogenes invasion, cytochalasin D, which disrupts actin polymerization, and wortmannin, which blocks phosphatidylinositol (PI) 3-kinase activity, did not block ERK-2 activation by wild-type L. monocytogenes and hly mutants. However, genistein, an inhibitor of tyrosine kinases, and PD98059 both blocked invasion and decreased ERK-2 activation. These results suggest that MEK-1 and ERK-2 activities are essential for L. monocytogenes invasion into host epithelial cells. This is the first report to show that a MAP kinase pathway is required for bacterial invasion.
Tang
P
P
Department of Microbiology and Immunology, University of British Columbia, Vancouver, Canada.
Sutherland
C L
CL
Gold
M R
MR
Finlay
B B
BB
D000730:Androstadienes / Q000494:pharmacology; D001427:Bacterial Toxins; D015638:Cytochalasin D / Q000494:pharmacology; D004847:Epithelial Cells / Q000382:microbiology; D005419:Flavonoids / Q000494:pharmacology; D019833:Genistein / Q000494:pharmacology; D006367:HeLa Cells; D006360:Heat-Shock Proteins / Q000494:pharmacology; D006460:Hemolysin Proteins; D006801:Humans; D048031:JNK Mitogen-Activated Protein Kinases; D008089:Listeria monocytogenes / Q000502:physiology*; D048369:MAP Kinase Kinase 1; D048670:MAP Kinase Kinase 4; D019950:Mitogen-Activated Protein Kinase 1 / Q000502:physiology*; D020929:Mitogen-Activated Protein Kinase Kinases; D011494:Protein Kinases / Q000502:physiology; D017346:Protein Serine-Threonine Kinases / Q000502:physiology*; D011505:Protein-Tyrosine Kinases / Q000502:physiology*; D000077191:Wortmannin
D000730:Androstadienes; D001427:Bacterial Toxins; D005419:Flavonoids; D006360:Heat-Shock Proteins; D006460:Hemolysin Proteins; D015638:Cytochalasin D; D019833:Genistein; D011494:Protein Kinases; D011505:Protein-Tyrosine Kinases; D017346:Protein Serine-Threonine Kinases; D048031:JNK Mitogen-Activated Protein Kinases; D019950:Mitogen-Activated Protein Kinase 1; D048369:MAP Kinase Kinase 1; D048670:MAP Kinase Kinase 4; C482125:MAP2K1 protein, human; D020929:Mitogen-Activated Protein Kinase Kinases; C038705:hlyA protein, Listeria monocytogenes; C093973:2-(2-amino-3-methoxyphenyl)-4H-1-benzopyran-4-one; D000077191:Wortmannin