Differential ubiquitylation of the mineralocorticoid receptor is regulated by phosphorylation
Differential ubiquitylation of the mineralocorticoid receptor is regulated by phosphorylation
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DOI：
10.1096/fj.12-209924
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发表时间：
2012-10-01
期刊：
影响因子：
4.8
通讯作者：
Staub, Olivier
中科院分区：
文献类型：
--
作者：
Faresse, Nourdine;Vitagliano, Jean-Jacques;Staub, Olivier
醛固酮对盐皮质激素受体（MR）的刺激参与许多生理反应，包括Na+稳态、血压控制和心力衰竭。醛固酮与MR结合促进不同的翻译后修饰，这些修饰调节MR核转位、基因表达，最终调节受体降解。在这里，我们表明，醛固酮刺激快速磷酸化的MR通过ERK 1/2在肾上皮细胞中以剂量依赖性的方式（从0.1到10 nM）。这种磷酸化诱导MR表观分子量增加，最大向上移动30 kDa。引人注目的是，这些修饰对于调节MR泛素化状态至关重要。事实上，我们发现MR在其基础状态下是单泛素化的，并且这种状态由肿瘤抑制基因101（Tsg 101）维持。磷酸化导致MR/Tsg 101缔合的破坏和monoubiquitin去除。这些事件促使MR的聚泛蛋白依赖性不稳定和降解。通过ERK 1/2抑制或靶丝氨酸突变阻止MR磷酸化影响MR泛素化的顺序机制并抑制醛固酮介导的降解。我们的数据提供了一种新的醛固酮信号负反馈模型，涉及顺序磷酸化，monoubiquitin去除和随后的多泛素化/MR降解。Faresse，N.，Vitagliano，J. J.，Staub，O.盐皮质激素受体的差异泛素化受磷酸化调节。FASEB J.26，4373-4382（2012）。www.fasebj.org
Aldosterone stimulation of the mineralocorticoid receptor (MR) is involved in numerous physiological responses, including Na+ homeostasis, blood pressure control, and heart failure. Aldosterone binding to MR promotes different post-translational modifications that regulate MR nuclear translocation, gene expression, and finally receptor degradation. Here, we show that aldosterone stimulates rapid phosphorylation of MR via ERK1/2 in a dose-dependent manner (from 0.1 to 10 nM) in renal epithelial cells. This phosphorylation induces an increase of MR apparent molecular weight, with a maximal upward shift of 30 kDa. Strikingly, these modifications are critical for the regulation of the MR ubiquitylation state. Indeed, we find that MR is monoubiquitylated in its basal state, and this status is sustained by the tumor suppressor gene 101 (Tsg101). Phosphorylation leads to disruption of MR/Tsg101 association and monoubiquitin removal. These events prompt polyubiquitin-dependent destabilization of MR and degradation. Preventing MR phosphorylation by ERK1/2 inhibition or mutation of target serines affects the sequential mechanisms of MR ubiquitylation and inhibits the aldosterone-mediated degradation. Our data provide a novel model of negative feedback of aldosterone signaling, involving sequential phosphorylation, monoubiquitin removal and subsequent polyubiquitylation/degradation of MR.-Faresse, N., Vitagliano, J.-J., Staub, O. Differential ubiquitylation of the mineralocorticoid receptor is regulated by phosphorylation. FASEB J. 26, 4373-4382 (2012). www.fasebj.org