BoseDasgupta Somdeb, Moes Suzette, Jenoe Paul, Pieters Jean
Biozentrum, University of Basel, Switzerland.
FEBS J. 2015 Apr;282(7):1167-81. doi: 10.1111/febs.13214. Epub 2015 Feb 27.
The induction of macropinocytosis in macrophages during an inflammatory response is important for clearance of pathogenic microbes as well as the generation of appropriate immune responses. Recent data suggest that cytokine stimulation of macrophages induces macropinocytosis through phosphorylation of the protein coronin 1, thereby redistributing coronin 1 from the cell cortex to the cytoplasm followed by the activation of phosphoinositol-3 (PI-3) kinase. However, how coronin 1 phosphorylation regulates these processes remains unclear. We here define an essential role for 14-3-3ζ in cytokine-induced and coronin-1-dependent macropinocytosis in macrophages. We found that, upon stimulation, phosphorylated coronin 1 transiently associated with 14-3-3ζ and receptor of activated C kinase 1 (RACK1). Importantly, downregulation of 14-3-3ζ, but not RACK1, prevented relocation of coronin 1, as well as the induction of PI-3 kinase activity and thereby macropinocytosis upon cytokine stimulation. Together these data define an essential role for 14-3-3ζ in the regulation of macropinocytosis in macrophages upon cytokine stimulation through modulation of the localization of coronin 1.
炎症反应期间巨噬细胞中巨胞饮作用的诱导对于清除致病微生物以及产生适当的免疫反应至关重要。最近的数据表明，细胞因子对巨噬细胞的刺激通过蛋白冠蛋白1的磷酸化诱导巨胞饮作用，从而使冠蛋白1从细胞皮质重新分布到细胞质，随后激活磷酸肌醇-3（PI-3）激酶。然而，冠蛋白1磷酸化如何调节这些过程仍不清楚。我们在此确定了14-3-3ζ在巨噬细胞中细胞因子诱导的和冠蛋白1依赖性巨胞饮作用中的关键作用。我们发现，受到刺激后，磷酸化的冠蛋白1与14-3-3ζ和活化C激酶1受体（RACK1）短暂结合。重要的是，下调14-3-3ζ而不是RACK1可阻止冠蛋白1的重新定位，以及PI-3激酶活性的诱导，从而阻止细胞因子刺激后的巨胞饮作用。这些数据共同确定了14-3-3ζ在通过调节冠蛋白1的定位来调控细胞因子刺激后巨噬细胞巨胞饮作用中的关键作用。
