14-3-3 proteins modulate the expression of epithelial Na+ channels by phosphorylation-dependent interaction with Nedd4-2 ubiquitin ligase
14-3-3 proteins modulate the expression of epithelial Na+ channels by phosphorylation-dependent interaction with Nedd4-2 ubiquitin ligase
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DOI：
10.1074/jbc.m412884200
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发表时间：
2005-04-01
影响因子：
4.8
通讯作者：
Isobe, T
中科院分区：
文献类型：
--
作者：
Ichimura, T;Yamamura, H;Isobe, T
泛素E3蛋白连接酶Nedd 4 -2是上皮钠通道ENaC的生理调节剂，ENaC是跨上皮Na+转运所必需的，并与Liddle综合征（一种常染色体显性人类盐敏感性高血压疾病）相关。Nedd 4 -2功能通过血清和糖皮质激素诱导的蛋白激酶（Sgk 1）的磷酸化负调节，其作为抑制ENaC的泛素化依赖性降解的机制。我们在这里报告，14-3-3蛋白参与这一调控过程，通过直接与磷酸化形式的人Nedd 4 -2（KIAA 0439的人基因产物，称为hNedd 4 -2）的相互作用。这种相互作用依赖于Sgk 1催化的hNedd 4 -2在Ser-468的磷酸化。我们发现，这种相互作用保留了Sgk 1刺激的ENaC依赖性Na+电流的活性，同时破坏了这种相互作用，降低了非洲爪蟾卵母细胞表面的ENaC密度，这可能是通过增强Nedd 4 -2介导的泛素化导致ENaC降解。我们的研究结果表明，14-3-3蛋白调节ENaC的细胞表面密度与Sgk 1激酶合作，保持hNedd 4 -2在一个非活性的磷酸化状态。
The ubiquitin E3 protein ligase Nedd4-2 is a physiological regulator of the epithelial sodium channel ENaC, which is essential for transepithelial Na+ transport and is linked to Liddle's syndrome, an autosomal dominant disorder of human salt-sensitive hypertension. Nedd4-2 function is negatively regulated by phosphorylation via a serum- and glucocorticoid-inducible protein kinase (Sgk1), which serves as a mechanism to inhibit the ubiquitination-dependent degradation of ENaC. We report here that 14-3-3 proteins participate in this regulatory process through a direct interaction with a phosphorylated form of human Nedd4-2 (a human gene product of KIAA0439, termed hNedd4-2). The interaction is dependent on Sgk1-catalyzed phosphorylation of hNedd4-2 at Ser-468. We found that this interaction preserved the activity of the Sgk1-stimulated ENaC-dependent Na+ current while disrupting the interaction decreased ENaC density on the Xenopus laevis oocytes surface possibly by enhancing Nedd4-2-mediated ubiquitination that leads to ENaC degradation. Our findings suggest that 14-3-3 proteins modulate the cell surface density of ENaC cooperatively with Sgk1 kinase by maintaining hNedd4-2 in an inactive phosphorylated state.