Polycystin-1, STAT6, and pathway that transduces P100 function in a ciliary mechanosensation and is activated in polycystic kidney disease
Polycystin-1, STAT6, and pathway that transduces P100 function in a ciliary mechanosensation and is activated in polycystic kidney disease
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DOI：
10.1016/j.devcel.2005.12.005
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发表时间：
2006-01-01
影响因子：
11.8
通讯作者：
Weimbs, T
中科院分区：
文献类型：
--
作者：
Low, SH;Vasanth, S;Weimbs, T
原生纤毛与常染色体显性遗传性多囊肾病(ADPKD)的发病机制有关，ADPKD由多囊蛋白-1(PC1)缺陷引起，但PC1的功能仍知之甚少。在这里，我们表明PC1经历了蛋白水解性切割，导致其细胞质尾巴的核移位。PC1 Tail与转录因子STAT6和辅活化子P100相互作用，刺激STAT6依赖的基因表达。正常情况下，STAT6定位于肾上皮细胞的初级纤毛。心尖液体流动的停止会导致STAT6的核移位。ADPKD中的囊性衬里细胞显示核STAT6、P100和PC1尾巴水平升高。外源表达人PC1尾巴导致斑马鱼胚胎形成肾囊。这些结果确定了纤毛在机械信号转导涉及PC1的基因表达变化中的新机制，并表明这一途径在ADPKD中被不适当地激活。
Primary cilia are implicated in the pathogenesis of autosomal-dominant polycystic kidney disease (ADPKD), which results from defects in polycystin-1 (PC1), but the function of PC1 remains poorly understood. Here, we show that PC1 undergoes proteolytic cleavage that results in nuclear translocation of its cytoplasmic tail. The PC1 tail interacts with the transcription factor STAT6 and the coactivator P100, and it stimulates STAT6-dependent gene expression. Under normal conditions, STAT6 localizes to primary cilia of renal epithelial cells. Cessation of apical fluid flow results in nuclear translocation of STAT6. Cyst-lining cells in ADPKD exhibit elevated levels of nuclear STAT6, P100, and the PC1 tail. Exogenous expression of the human PC1 tail results in renal cyst formation in zebrafish embryos. These results identify a novel mechanism of cilia function in the transduction of a mechanical signal to changes of gene expression involving PC1 and show that this pathway is inappropriately activated in ADPKD.