Smad ubiquitylation regulatory factor 1 promotes LIM-homeobox gene 9 degradation and represses testosterone production in Leydig cells
Smad ubiquitylation regulatory factor 1 promotes LIM-homeobox gene 9 degradation and represses testosterone production in Leydig cells
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Smad 泛素化调节因子 1 促进 LIM-同源盒基因 9 降解并抑制 Leydig 细胞中睾酮的产生
DOI：
10.1096/fj.201701480r
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发表时间：
2018-09-01
期刊：
影响因子：
4.8
通讯作者：
Zhang, Lingqiang
中科院分区：
文献类型：
--
作者：
Hu, Fan;Zhu, Qiong;Zhang, Lingqiang
睾酮对精子发生和男性第二性征的维持至关重要。LIM-homeobox基因9 （Lhx9）是一个重要的转录因子，在睾丸发育和睾酮产生中不可或缺；然而，Lhx9的翻译后修饰在很大程度上是未知的。在这里，据我们所知，我们首次证明了Lhx9蛋白水平在暴露于促性腺激素的人绒毛膜间质细胞中增加，并且可以多泛素化。我们发现Smad泛素化调节因子1 (Smurf1)，一种E3泛素连接酶，靶向Lhx9进行泛素介导的蛋白酶体降解，从而负向调节其功能。增加Smurf1降低Lhx9水平，抑制甾体生成因子1的Lhx9转激活能力[核受体亚家族5，A组，成员1 (NR5A1)]。相反，Smurf1的缺失导致Lhx9蛋白的表达增加，睾酮生物合成相关基因转录物[NR5A1，类固醇急性调节蛋白，CYP17A1，羟基-5-类固醇脱氢酶，羟基-5-类固醇脱氢酶异构酶6，羟基类固醇（17-）脱氢酶3]和睾丸素在间质细胞中的产生增加。此外，我们发现Smurf1基因敲除小鼠表现出更高水平的Lhx9蛋白和类固醇生成，从而导致血清睾酮浓度升高。这些发现表明Smurf1促进Lhx9泛素化，并直接参与间质细胞中睾酮的产生。我们的研究结果为睾酮水平稳态中的分子事件提供了新的见解，并可能为睾酮调节提供新的靶点。胡峰，朱强，孙斌，崔超，李超，张磊。Smad泛素化调节因子1促进间质细胞lim - homobox基因9降解和抑制睾酮产生。
Testosterone is essential for spermatogenesis and the maintenance of secondary sexual characteristics in males. An important transcription factor, LIM-homeobox gene 9 (Lhx9) is indispensable for testis development and testosterone production; however, post-translational modifications of Lhx9 are largely unknown. Here, for the first time to our knowledge, we demonstrate that the level of Lhx9 protein increases in human chorionic gonadotropin-exposed Leydig cells and can be polyubiquitylated. We found that Smad ubiquitylation regulatory factor 1 (Smurf1), an E3 ubiquitin ligase, targets Lhx9 for ubiquitin-mediated proteasome degradation, thereby negatively modulating its function. Increasing Smurf1 decreases the level of Lhx9 and inhibits the Lhx9 transactivation capacity of steroidogenic factor 1 [nuclear receptor subfamily 5, group A, member 1 (NR5A1)]. In contrast, the depletion of Smurf1 leads to increased expression of Lhx9 protein and enhances testosterone biosynthesis-related gene transcripts [NR5A1, steroidogenic acute regulatory protein, CYP17A1, hydroxy--5-steroid dehydrogenase, hydroxy--5-steroid dehydrogenase isomerase 6, and hydroxysteroid (17-) dehydrogenase 3] and testosterone production in Leydig cells. Furthermore, we found that Smurf1 knockout mice exhibit higher levels of Lhx9 protein and steroidogenesis, which leads to increased serum testosterone concentration. These findings reveal that Smurf1 promotes Lhx9 ubiquitylation and is involved in testosterone production in Leydig cells directly. Our results provide new insights into the molecular events that play a role in the homeostasis of testosterone levels and may provide a new target for testosterone regulation.Hu, F., Zhu, Q., Sun, B., Cui, C., Li, C., Zhang, L. Smad ubiquitylation regulatory factor 1 promotes LIM-homeobox gene 9 degradation and represses testosterone production in Leydig cells.