Potassium depletion stimulates Na-Cl cotransporter via phosphorylation and inactivation of the ubiquitin ligase Kelch-like 3.
Potassium depletion stimulates Na-Cl cotransporter via phosphorylation and inactivation of the ubiquitin ligase Kelch-like 3.
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DOI：
10.1016/j.bbrc.2016.10.127
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发表时间：
2016-11
影响因子：
3.1
通讯作者：
Shibata, Shigeru
中科院分区：
文献类型：
--
作者：
Ishizawa, Kenichi;Xu, Ning;Loffing, Johannes;Lifton, Richard P.;Fujita, Toshiro;Uchida, Shunya;Shibata, Shigeru
Kelch-like 3 (KLHL3) 是 E3 泛素连接酶复合物的一个组成部分，该复合物通过靶向无赖氨酸 (WNK) 激酶进行降解来调节血压。 KLHL3 突变导致肾盐重吸收持续增加，K+ 分泌受损，导致高血压和高钾血症。尽管临床研究表明膳食 K+ 摄入量会影响血压，但其机制尚不清楚。在这项研究中，我们证明 KLHL3 泛素连接酶复合物参与肾脏中低 K+ 介导的 Na-Cl 协同转运蛋白 (NCC) 的激活。在吃低 K+ 饮食的小鼠的远端曲小管中，我们发现 S433 (KLHL3S433-P) 处的 KLHL3 磷酸化增加，这是一种损害 WNK 结合的修饰，并且还降低了 KLHL3 总水平。这些变化伴随着靶底物WNK4的积累，以及下游激酶SPAK（STE20/SPS1相关的富含脯氨酸丙氨酸的蛋白激酶）和OSR1（氧化应激反应1）的激活，导致NCC磷酸化及其在质膜上的积累。 S433 磷酸化增加的原因是活性磷酸化蛋白激酶 C（但不是蛋白激酶 A）水平增加，直接磷酸化 S433。此外，在表达 KLHL3 和 WNK4 的 HEK 细胞中，我们发现佛波醇 12-肉豆蔻酸酯 13-乙酸酯激活蛋白激酶 C 会诱导 KLHL3S433-P，并通过消除其泛素化来增加 WNK4 水平。这些数据证明了 KLHL3 在低 K+ 介导的 NCC 诱导中的作用；这种生理适应减少了远端电Na+重吸收，防止肾K+进一步流失，但促进血压升高。
Kelch-like 3 (KLHL3) is a component of an E3 ubiquitin ligase complex that regulates blood pressure by targeting With-No-Lysine (WNK) kinases for degradation. Mutations in KLHL3 cause constitutively increased renal salt reabsorption and impaired K+ secretion, resulting in hypertension and hyperkalemia. Although clinical studies have shown that dietary K+ intake affects blood pressure, the mechanisms have been obscure. In this study, we demonstrate that the KLHL3 ubiquitin ligase complex is involved in the low-K+-mediated activation of Na-Cl cotransporter (NCC) in the kidney. In the distal convoluted tubules of mice eating a low-K+ diet, we found increased KLHL3 phosphorylation at S433 (KLHL3S433-P), a modification that impairs WNK binding, and also reduced total KLHL3 levels. These changes are accompanied by the accumulation of the target substrate WNK4, and activation of the downstream kinases SPAK (STE20/SPS1-related proline-alanine-rich protein kinase) and OSR1 (oxidative stress-responsive 1), resulting in NCC phosphorylation and its accumulation at the plasma membrane. Increased phosphorylation of S433 was explained by increased levels of active, phosphorylated protein kinase C (but not protein kinase A), which directly phosphorylates S433. Moreover, in HEK cells expressing KLHL3 and WNK4, we showed that the activation of protein kinase C by phorbol 12-myristate 13-acetate induces KLHL3S433-P and increases WNK4 levels by abrogating its ubiquitination. These data demonstrate the role of KLHL3 in low-K+-mediated induction of NCC; this physiologic adaptation reduces distal electrogenic Na+ reabsorption, preventing further renal K+ loss but promoting increased blood pressure.
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影响因子：
64.8
作者：
Boyden, Lynn M.;Choi, Murim;Choate, Keith A.;Nelson-Williams, Carol J.;Farhi, Anita;Toka, Hakan R.;Tikhonova, Irina R.;Bjornson, Robert;Mane, Shrikant M.;Colussi, Giacomo;Lebel, Marcel;Gordon, Richard D.;Semmekrot, Ben A.;Poujol, Alain;Valimaki, Matti J.;De Ferrari, Maria E.;Sanjad, Sami A.;Gutkin, Michael;Karet, Fiona E.;Tucci, Joseph R.;Stockigt, Jim R.;Keppler-Noreuil, Kim M.;Porter, Craig C.;Anand, Sudhir K.;Whiteford, Margo L.;Davis, Ira D.;Dewar, Stephanie B.;Bettinelli, Alberto;Fadrowski, Jeffrey J.;Belsha, Craig W.;Hunley, Tracy E.;Nelson, Raoul D.;Trachtman, Howard;Cole, Trevor R. P.;Pinsk, Maury;Bockenhauer, Detlef;Shenoy, Mohan;Vaidyanathan, Priya;Foreman, John W.;Rasoulpour, Majid;Thameem, Farook;Al-Shahrouri, Hania Z.;Radhakrishnan, Jai;Gharavi, Ali G.;Goilav, Beatrice;Lifton, Richard P.
通讯作者：
Lifton, Richard P.
影响因子：
4
作者：
Richardson, Ciaran;Rafiqi, Fatema H.;Alessi, Dario R.
通讯作者：
Alessi, Dario R.
影响因子：
158.5
作者：
Mente, Andrew;O'Donnell, Martin J.;Yusuf, Salim
通讯作者：
Yusuf, Salim
Cullin-3突变的表征会导致严重的家族性高血压和高潮血症。
影响因子：
11.1
作者：
Schumacher FR;Siew K;Zhang J;Johnson C;Wood N;Cleary SE;Al Maskari RS;Ferryman JT;Hardege I;Yasmin;Figg NL;Enchev R;Knebel A;O'Shaughnessy KM;Kurz T
通讯作者：
Kurz T
DOI：
10.1042/bj20121903
发表时间：
2013-04-01
期刊：
The Biochemical journal
影响因子：
--
作者：
Ohta A;Schumacher FR;Mehellou Y;Johnson C;Knebel A;Macartney TJ;Wood NT;Alessi DR;Kurz T
通讯作者：
Kurz T