Characterisation of the Cullin-3 mutation that causes a severe form of familial hypertension and hyperkalaemia.
Characterisation of the Cullin-3 mutation that causes a severe form of familial hypertension and hyperkalaemia.
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Cullin-3突变的表征会导致严重的家族性高血压和高潮血症。
DOI：
10.15252/emmm.201505444
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发表时间：
2015-10
影响因子：
11.1
通讯作者：
Kurz T
中科院分区：
文献类型：
--
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
Cullin-3 的外显子 9 缺失（CUL3，残基 403-459：CUL3Δ403-459）会导致 IIE 型假性醛固酮增多症 (PHA2E)，这是一种严重的家族性高钾血症和高血压 (FHHt)。 CUL3 结合 RING 蛋白 RBX1 和各种底物接头，形成 Cullin-RING-泛素-连接酶复合物。 CUL3-RBX1 与 KLHL3 结合，使 WNK 激酶泛素化，促进其泛素介导的蛋白酶体降解。由于 WNK 激酶激活 Na/Cl 协同转运蛋白以促进盐潴留，因此 CUL3 可以调节血压。 KLHL3 和 WNK 激酶的突变通过破坏 Cullin-RING 连接酶的形成而导致 PHA2。我们在此报告，PHA2E 突变体 CUL3Δ403-459 泛素化 WNK 的能力受到严重损害，这可能是由于结构灵活性的改变所致。相反，CUL3Δ403-459 自动泛素化并失去与两个重要的 Cullin 调节因子的相互作用：COP9 信号体和 CAND1。 CUL3WT/Δ403-459 的新型敲入小鼠模型密切再现了人类 PHA2E 表型。这些小鼠还表现出动脉脉搏波形的变化，表明血管对其高血压的影响在之前的 FHHt 模型中没有报道过。这些发现可以解释与 KLHL3 或 WNK 激酶中报道的相比，由 CUL3 突变引起的 FHHt 表型的严重性。
Deletion of exon 9 from Cullin-3 (CUL3, residues 403–459: CUL3Δ403–459) causes pseudohypoaldosteronism type IIE (PHA2E), a severe form of familial hyperkalaemia and hypertension (FHHt). CUL3 binds the RING protein RBX1 and various substrate adaptors to form Cullin-RING-ubiquitin-ligase complexes. Bound to KLHL3, CUL3-RBX1 ubiquitylates WNK kinases, promoting their ubiquitin-mediated proteasomal degradation. Since WNK kinases activate Na/Cl co-transporters to promote salt retention, CUL3 regulates blood pressure. Mutations in both KLHL3 and WNK kinases cause PHA2 by disrupting Cullin-RING-ligase formation. We report here that the PHA2E mutant, CUL3Δ403–459, is severely compromised in its ability to ubiquitylate WNKs, possibly due to altered structural flexibility. Instead, CUL3Δ403–459 auto-ubiquitylates and loses interaction with two important Cullin regulators: the COP9-signalosome and CAND1. A novel knock-in mouse model of CUL3WT/Δ403–459 closely recapitulates the human PHA2E phenotype. These mice also show changes in the arterial pulse waveform, suggesting a vascular contribution to their hypertension not reported in previous FHHt models. These findings may explain the severity of the FHHt phenotype caused by CUL3 mutations compared to those reported in KLHL3 or WNK kinases.