Disease-causing mutations in KLHL3 impair its effect on WNK4 degradation.
Disease-causing mutations in KLHL3 impair its effect on WNK4 degradation.
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DOI：
10.1016/j.febslet.2013.04.032
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发表时间：
2013-06-19
期刊：
影响因子：
3.5
通讯作者：
Peng JB
中科院分区：
文献类型：
--
作者：
Wu G;Peng JB
非赖氨酸激酶4(WNK4)和泛素E3连接酶复合体成分kelch-like 3(KLHL3)的突变都会导致假性醛固酮减少症II(PHAII)，这是一种遗传性高血压。我们确定了在非洲爪哇卵母细胞中WNK4或其效应物是否受KLHL3的调控。KLHL3通过降低WNK4蛋白丰度而抑制WNK4对钠-氯−共转运体(NCC)的正向作用，而不直接降低NCC和下游蛋白OSR1的丰度。KLHL3诱导WNK4泛素化和降解。KLHL3对WNK4降解的影响被显性负型cullin 3所阻断。KLHL3的5个PHAII突变都干扰了对WNK4的调节。我们认为KLHL3是泛素E3连接酶复合体中WNK4的底物接头。
Mutations in with-no-lysine (K) kinase 4 (WNK4) and a ubiquitin E3 ligase complex component kelch-like 3 (KLHL3) both cause pseudohypoaldosteronism II (PHAII), a hereditary form of hypertension. We determined whether WNK4 or its effector is regulated by KLHL3 in Xenopus oocytes. KLHL3 inhibited the positive effect of WNK4 on Na+-Cl− cotransporter (NCC) by decreasing WNK4 protein abundance without decreasing that of NCC and the downstream kinase OSR1 directly. Ubiquitination and degradation of WNK4 were induced by KLHL3. The effect of KLHL3 on WNK4 degradation was blocked by a dominant negative form of cullin 3. All five PHAII mutations of KLHL3 tested disrupted the regulation on WNK4. We conclude that KLHL3 is a substrate adaptor for WNK4 in a ubiquitin E3 ligase complex.