Interferon alpha inhibits a Src-mediated pathway necessary for Shigella-induced cytoskeletal rearrangements in epithelial cells.
Shigella flexneri, the causative agent of bacillary dysentery, has the ability to enter nonphagocytic cells. The interferon (IFN) family of cytokines was found to inhibit Shigella invasion of cultured epithelial cells. We show here that IFN-alpha inhibits a Src-dependent signaling cascade triggered by Shigella that leads to the reorganization of the host cell cytoskeleton. Immunofluorescence studies showed that IFN-alpha inhibits Shigella-induced actin polymerization required for bacterial entry into cells. Phosphorylation of cortactin, a Src-substrate specifically tyrosyl-phosphorylated during Shigella entry, was inhibited by IFN-alpha. Overexpression of a dominant interfering form of pp60c-src led to inhibition of Shigella-induced cytoskeletal rearrangements and decreased cortactin phosphorylation indicating a role for Src in Shigella entry. Also, Shigella uptake in cells that expressed constitutively active Src was unaffected by IFN-alpha treatment. We conclude that Src kinase activity is necessary for Shigella invasion of epithelial cells and that IFN-alpha inhibits this Src-dependent signaling pathway.
Duménil
G
G
Unité de Génétique Humaine, INSERM U276.
Olivo
J C
JC
Pellegrini
S
S
Fellous
M
M
Sansonetti
P J
PJ
Nhieu
G T
GT
D000199:Actins / Q000378:metabolism; D051356:Cortactin; D003599:Cytoskeleton / Q000378:metabolism*; D004847:Epithelial Cells / Q000378:metabolism / Q000382:microbiology*; D006367:HeLa Cells; D006801:Humans; D016898:Interferon-alpha / Q000378:metabolism*; D008840:Microfilament Proteins / Q000378:metabolism; D010766:Phosphorylation; D016392:Proto-Oncogene Proteins pp60(c-src) / Q000235:genetics* / Q000378:metabolism; D012763:Shigella flexneri / Q000378:metabolism*; D015398:Signal Transduction / Q000502:physiology; D014443:Tyrosine / Q000378:metabolism
D000199:Actins; C495868:CTTN protein, human; D051356:Cortactin; D016898:Interferon-alpha; D008840:Microfilament Proteins; D014443:Tyrosine; D016392:Proto-Oncogene Proteins pp60(c-src)