Cheng Jinke, Kang Xunlei, Zhang Sui, Yeh Edward T H
Department of Cardiology, The University of Texas MD Anderson Cancer Center, The University of Texas, Houston Health Science Center, Houston, TX 77030, USA.
Cell. 2007 Nov 2;131(3):584-95. doi: 10.1016/j.cell.2007.08.045.
SUMOylation is a dynamic process, catalyzed by SUMO-specific ligases and reversed by Sentrin/SUMO-specific proteases (SENPs). The physiologic consequences of SUMOylation and deSUMOylation are not fully understood. Here we investigate the phenotypes of mice lacking SENP1 and find that SENP1(-/-) embryos show severe fetal anemia stemming from deficient erythropoietin (Epo) production and die midgestation. We determine that SENP1 controls Epo production by regulating the stability of hypoxia-inducible factor 1alpha (HIF1alpha) during hypoxia. Hypoxia induces SUMOylation of HIF1alpha, which promotes its binding to a ubiquitin ligase, von Hippel-Lindau (VHL) protein, through a proline hydroxylation-independent mechanism, leading to its ubiquitination and degradation. In SENP1(-/-) MEFs, hypoxia-induced transcription of HIF1alpha-dependent genes such as vascular endothelial growth factor (VEGF) and glucose transporter 1 (Glut-1) is markedly reduced. These results show that SENP1 plays a key role in the regulation of the hypoxic response through regulation of HIF1alpha stability and that SUMOylation can serve as a direct signal for ubiquitin-dependent degradation.
小泛素样修饰（SUMOylation）是一个动态过程，由SUMO特异性连接酶催化，并由Sentrin/SUMO特异性蛋白酶（SENPs）逆转。SUMOylation和去SUMOylation的生理后果尚未完全了解。在这里，我们研究了缺乏SENP1的小鼠的表型，发现SENP1（-/-）胚胎因促红细胞生成素（Epo）产生不足而出现严重的胎儿贫血，并在妊娠中期死亡。我们确定SENP1通过在缺氧期间调节缺氧诱导因子1α（HIF1α）的稳定性来控制Epo的产生。缺氧诱导HIF1α的SUMOylation，通过脯氨酸羟化非依赖性机制促进其与泛素连接酶冯·希佩尔-林道（VHL）蛋白的结合，导致其泛素化和降解。在SENP1（-/-）小鼠胚胎成纤维细胞（MEFs）中，缺氧诱导的HIF1α依赖性基因如血管内皮生长因子（VEGF）和葡萄糖转运蛋白1（Glut-1）的转录明显减少。这些结果表明，SENP1通过调节HIF1α的稳定性在缺氧反应的调节中起关键作用，并且SUMOylation可以作为泛素依赖性降解的直接信号。
