The role for HNF-1beta-targeted collectrin in maintenance of primary cilia and cell polarity in collecting duct cells.
The role for HNF-1beta-targeted collectrin in maintenance of primary cilia and cell polarity in collecting duct cells.
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DOI：
10.1371/journal.pone.0000414
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发表时间：
2007-05-02
期刊：
影响因子：
3.7
通讯作者：
Makino H
中科院分区：
文献类型：
--
作者：
Zhang Y;Wada J;Yasuhara A;Iseda I;Eguchi J;Fukui K;Yang Q;Yamagata K;Hiesberger T;Igarashi P;Zhang H;Wang H;Akagi S;Kanwar YS;Makino H
Collectrin是血管紧张素转换酶2(ACE2)的同系物，是一种I型跨膜蛋白，我们首次报道它定位于集合管细胞的细胞质和顶膜。最近，两项针对小鼠体内胶原素靶向干扰的独立研究导致了肾脏氨基酸摄取的严重和普遍缺陷。据报道，Collectrin受hnf-1α的转录调控，它只表达在近端的小管上，定位于刷状缘膜的管腔一侧。胶原蛋白缺乏与腔膜上多个氨基酸转运体的减少有关。在目前的研究中，我们描述了Colltrin是hnf-1β的靶标，并在肾脏集合管细胞的初级纤毛中大量表达。Collectrin还定位于靠近基底体区域的小泡中，并与γ-肌动蛋白-肌球蛋白II-A、SNARE和多囊蛋白-2-极星复合体结合，所有这些都参与了小泡和膜蛋白的细胞内和纤毛运动。用集合素siRNA处理mIMCD3细胞，可导致纤毛形成缺陷，细胞增殖和凋亡增加，原代纤毛中多囊蛋白-2消失。后肾培养中集合素基因的表达受到抑制，导致输尿管芽支形成多个纵行包囊。综上所述，纤毛囊性改变和缺陷纤毛的形成干扰了集合素的功能，提示初级纤毛膜蛋白的循环、初级纤毛的维持和集合管细胞的细胞极性是必要的。在集合管细胞原代纤毛中表达的hnf-1β和多囊肾病基因之间存在转录层次关系，Collectrin是hnf-1β调控的基因之一。
Collectrin, a homologue of angiotensin converting enzyme 2 (ACE2), is a type I transmembrane protein, and we originally reported its localization to the cytoplasm and apical membrane of collecting duct cells. Recently, two independent studies of targeted disruption of collectrin in mice resulted in severe and general defects in renal amino acid uptake. Collectrin has been reported to be under the transcriptional regulation by HNF-1α, which is exclusively expressed in proximal tubules and localized at the luminal side of brush border membranes. The deficiency of collectrin was associated with reduction of multiple amino acid transporters on luminal membranes. In the current study, we describe that collectrin is a target of HNF-1β and heavily expressed in the primary cilium of renal collecting duct cells. Collectrin is also localized in the vesicles near the peri-basal body region and binds to γ-actin-myosin II-A, SNARE, and polycystin-2-polaris complexes, and all of these are involved in intracellular and ciliary movement of vesicles and membrane proteins. Treatment of mIMCD3 cells with collectrin siRNA resulted in defective cilium formation, increased cell proliferation and apoptosis, and disappearance of polycystin-2 in the primary cilium. Suppression of collectrin mRNA in metanephric culture resulted in the formation of multiple longitudinal cysts in ureteric bud branches. Taken together, the cystic change and formation of defective cilium with the interference in the collectrin functions would suggest that it is necessary for recycling of the primary cilia-specific membrane proteins, the maintenance of the primary cilia and cell polarity of collecting duct cells. The transcriptional hierarchy between HNF-1β and PKD (polycystic kidney disease) genes expressed in the primary cilia of collecting duct cells has been suggested, and collectrin is one of such HNF-1β regulated genes.
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DOI：
10.1073/pnas.0402354101
发表时间：
2004-06-08
影响因子：
11.1
作者：
Mykytyn, K;Mullins, RF;Sheffield, VC
通讯作者：
Sheffield, VC
影响因子：
4.1
作者：
Buxton, P;Zhang, XM;Rowe, T
通讯作者：
Rowe, T
影响因子：
64.8
作者：
Mochizuki, T;Saijoh, Y;Yokoyama, T
通讯作者：
Yokoyama, T
影响因子：
15.9
作者：
Hou, XY;Mrug, M;Guay-Woodford, LM
通讯作者：
Guay-Woodford, LM
影响因子：
11.4
作者：
Köttgen, M;Benzing, T;Walz, G
通讯作者：
Walz, G