Modulation of chloride secretory responses and barrier function of intestinal epithelial cells by the Salmonella effector protein SigD
Modulation of chloride secretory responses and barrier function of intestinal epithelial cells by the Salmonella effector protein SigD
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DOI：
10.1152/ajpcell.00413.2003
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发表时间：
2004-10-01
影响因子：
5.5
通讯作者：
Barrett, KE
中科院分区：
文献类型：
--
作者：
Bertelsen, LS;Paesold, G;Barrett, KE
沙门氏菌效应蛋白SigD是一种肌醇磷酸磷酸酶，可抑制磷脂酰肌醇3 - 激酶依赖性信号传导。由于表皮生长因子（EGF）通过磷脂酰肌醇3 - 激酶抑制氯离子分泌，我们探究了沙门氏菌感染是否可能改变EGF的抑制作用。正如预期的那样，EGF抑制卡巴胆碱在T - 84上皮细胞中诱导的氯离子分泌。野生型（WT）而非sigD（ - ）突变型鼠伤寒沙门氏菌SL1344感染会降低卡巴胆碱刺激的氯离子分泌。此外，野生型而非sigD（ - ）沙门氏菌会降低EGF对卡巴胆碱刺激的氯离子分泌的抑制作用。sigD的互补恢复了突变型沙门氏菌逆转EGF抑制作用的能力。在感染野生型或突变型沙门氏菌的细胞中，EGF诱导的EGF受体磷酸化相似，并且野生型和sigD（ - ）沙门氏菌都没有改变磷脂酰肌醇3 - 激酶的p85亚基向EGF受体的募集，这意味着SigD在这些信号事件的下游起作用。此外，与感染sigD（ - ）沙门氏菌的细胞相比，感染野生型沙门氏菌的细胞跨上皮电阻下降得更快，这表明SigD在降低屏障功能方面具有早期作用，可能是通过激活蛋白激酶C。我们得出结论，沙门氏菌效应蛋白SigD可能在这种微生物引起的疾病发病机制中起关键作用。
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.