Pdcd10-Stk24/25 complex controls kidney water reabsorption by regulating Aqp2 membrane targeting.
Pdcd10-Stk24/25 complex controls kidney water reabsorption by regulating Aqp2 membrane targeting.
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Pdcd10-Stk24/25 复合物通过调节 Aqp2 膜靶向来控制肾脏水重吸收
DOI：
10.1172/jci.insight.142838
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发表时间：
2021-06-22
期刊：
影响因子：
8
通讯作者：
Zheng X
中科院分区：
文献类型：
--
作者：
Wang R;Wu ST;Yang X;Qian Y;Choi JP;Gao R;Song S;Wang Y;Zhuang T;Wong JJ;Zhang Y;Han Z;Lu HA;Alexander SI;Liu R;Xia Y;Zheng X
PDCD 10，也被称为CCM 3，是一种被发现与人类疾病脑海绵状血管畸形（CCM）相关的基因。PDCD 10与包括STK 24、STK 25和MST 4的GCKIII激酶形成复合物。在C.线虫和果蝇已经显示出PDCD 10-GCK III复合物在维持上皮完整性中的关键作用。在这里，我们发现，在肾小管中缺乏Pdcd 10或Stk 24/25的小鼠出现多尿，并显示出耗水量增加。虽然水通道蛋白基因的表达水平没有降低，但在Pdcd 10和Stk 24/25缺陷小鼠中，肾小管上皮细胞顶膜中总的和磷酸化的水通道蛋白2（Aqp 2）蛋白的水平降低。这种Aqp 2的丢失与Ezrin和磷酸化Ezrin、Radixin、Moesin（p-ERM）蛋白的表达和膜靶向增加以及受损的细胞内囊泡运输相关。厄洛替尼（一种促进胞吐和抑制胞吞的酪氨酸激酶抑制剂）治疗使Aqp 2蛋白的表达水平和膜丰度正常化，并部分挽救了在Pdcd 10缺陷小鼠中观察到的水重吸收缺陷。我们目前的研究确定了PDCD 10-STK-ERM信号通路作为一种潜在的新途径，通过调节肾脏中AQP 2的囊泡运输和蛋白丰度来控制水平衡。
PDCD10, also known as CCM3, is a gene found to be associated with the human disease cerebral cavernous malformations (CCMs). PDCD10 forms a complex with GCKIII kinases including STK24, STK25, and MST4. Studies in C. elegans and Drosophila have shown a pivotal role of the PDCD10-GCKIII complex in maintaining epithelial integrity. Here, we found that mice deficient of Pdcd10 or Stk24/25 in the kidney tubules developed polyuria and displayed increased water consumption. Although the expression levels of aquaporin genes were not decreased, the levels of total and phosphorylated aquaporin 2 (Aqp2) protein in the apical membrane of tubular epithelial cells were decreased in Pdcd10- and Stk24/25-deficient mice. This loss of Aqp2 was associated with increased expression and membrane targeting of Ezrin and phosphorylated Ezrin, Radixin, Moesin (p-ERM) proteins and impaired intracellular vesicle trafficking. Treatment with Erlotinib, a tyrosine kinase inhibitor promoting exocytosis and inhibiting endocytosis, normalized the expression level and membrane abundance of Aqp2 protein, and partially rescued the water reabsorption defect observed in the Pdcd10-deficient mice. Our current study identified the PDCD10-STK-ERM signaling pathway as a potentially novel pathway required for water balance control by regulating vesicle trafficking and protein abundance of AQP2 in the kidneys.
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影响因子：
21.3
作者：
Madsen CD;Hooper S;Tozluoglu M;Bruckbauer A;Fletcher G;Erler JT;Bates PA;Thompson B;Sahai E
通讯作者：
Sahai E
影响因子：
16.6
作者：
Ando F;Sohara E;Morimoto T;Yui N;Nomura N;Kikuchi E;Takahashi D;Mori T;Vandewalle A;Rai T;Sasaki S;Kondo Y;Uchida S
通讯作者：
Uchida S
影响因子：
4.6
作者：
Louvi, Angeliki;Nishimura, Sayoko;Guenel, Murat
通讯作者：
Guenel, Murat
影响因子：
13.6
作者：
Gaeggeler, HP;Gonzalez-Rodriguez, E;Rossier, BC
通讯作者：
Rossier, BC
影响因子：
81.5
作者：
Christ-Crain, Mirjam;Bichet, Daniel G.;Verkman, Alan S.
通讯作者：
Verkman, Alan S.