Modulation of chloride secretory responses and barrier function of intestinal epithelial cells by the Salmonella effector protein SigD.
The Salmonella effector protein SigD is an inositol phosphate phosphatase that inhibits phosphatidylinositol 3-kinase-dependent signaling. Because epidermal growth factor (EGF) inhibits chloride secretion via phosphatidylinositol 3-kinase, we explored whether Salmonella infection might modify the inhibitory effect of EGF. As expected, EGF inhibited chloride secretion induced by carbachol in T(84) epithelial cells. Infection with wild-type (WT) but not sigD(-) mutant S. typhimurium SL1344 decreased CCh-stimulated chloride secretion. Moreover, WT but not sigD(-) Salmonella reduced the inhibitory effect of EGF on carbachol-stimulated chloride secretion. Complementation of sigD restored the ability of mutant Salmonella to reverse the inhibitory effect of EGF. EGF-induced EGF receptor phosphorylation was similar in cells infected with either WT or mutant Salmonella, and neither WT nor sigD(-) Salmonella altered recruitment of the p85 subunit of phosphatidylinositol 3-kinase to EGF receptor, implying that SigD acts downstream of these signaling events. Furthermore, transepithelial resistance fell more rapidly in cells infected with WT vs. sigD(-) Salmonella, indicating an early role for SigD in reducing barrier function, perhaps via activation of protein kinase C. We conclude that the Salmonella bacterial effector protein SigD may play critical roles in the pathogenesis of disease caused by this microorganism.
Bertelsen
Lone S
LS
Department of Medicine, Division of Gastroenterology, UCSD Medical Center 8414, 200 W. Arbor Dr., San Diego, CA 92103-8414, USA.
Paesold
Günther
G
Marcus
Sandra L
SL
Finlay
Brett B
BB
Eckmann
Lars
L
Barrett
Kim E
KE
D000818:Animals; D001426:Bacterial Proteins / Q000378:metabolism*; D002460:Cell Line; D002712:Chlorides / Q000378:metabolism*; D004815:Epidermal Growth Factor / Q000502:physiology; D004847:Epithelial Cells / Q000382:microbiology* / Q000502:physiology; D066246:ErbB Receptors / Q000378:metabolism; D006801:Humans; D007150:Immunohistochemistry; D007413:Intestinal Mucosa / Q000382:microbiology* / Q000502:physiology; D012480:Salmonella Infections / Q000503:physiopathology*; D012486:Salmonella typhimurium / Q000472:pathogenicity; D015398:Signal Transduction / Q000502:physiology; D019108:Tight Junctions / Q000378:metabolism / Q000382:microbiology
D001426:Bacterial Proteins; D002712:Chlorides; C060972:SopB protein, Bacteria; D004815:Epidermal Growth Factor; D066246:ErbB Receptors; C489224:SopB protein, Salmonella