OS-9 interacts with hypoxia-inducible factor 1α and prolyl hydroxylases to promote oxygen-dependent degradation of HIF-1α
OS-9 interacts with hypoxia-inducible factor 1α and prolyl hydroxylases to promote oxygen-dependent degradation of HIF-1α
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DOI：
10.1016/j.molcel.2005.01.011
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发表时间：
2005-02-18
期刊：
影响因子：
16
通讯作者：
Semenza, GL
中科院分区：
文献类型：
--
作者：
Baek, JH;Mahon, PC;Semenza, GL
缺氧诱导因子1（HIF-1）是后生动物体内氧平衡的主要调节因子。HIF-1介导响应细胞氧合变化的基因转录变化。HIF-1 α亚基的半衰期由氧依赖性脯氨酰羟基化决定，这是结合von Hippel-Lindau蛋白（VHL）所必需的，VHL是E3泛素连接酶的识别组分，靶向HIF-1 α进行泛素化和降解。在这里，我们证明了OS-9，广泛表达的基因的蛋白质产物，与HIF-1 α和HIF-α脯氨酰羟化酶相互作用。OS-9功能获得性促进HIF-1 α羟基化、VHL结合、HIF-1 α的蛋白酶体降解和HIF-1介导的转录抑制。在非缺氧条件下，RNA干扰引起的OS-9功能丧失可增加HIF-1 α蛋白水平、HIF-1介导的转录和VEGF mRNA表达。这些数据表明，OS-9是一个多蛋白复合物的重要组成部分，以O-2依赖的方式调节HIF-1 α水平。
Hypoxia-inducible factor 1 (HIF-1) functions as a master regulator of oxygen homeostasis in metazoan species. HIF-1 mediates changes in gene transcription in response to changes in cellular oxygenation. The half-life of the HIF-1alpha subunit is determined by oxygen-dependent prolyl hydroxylation, which is required for binding of the von Hippel-Lindau protein (VHL), the recognition component of an E3 ubiquitin ligase that targets HIF-1alpha for ubiquitination and degradation. Here, we demonstrate that OS-9, the protein product of a widely expressed gene, interacts with both HIF-1alpha and HIF-alpha prolyl hydroxylases. OS-9 gain-of-function promotes HIF-1alpha hydroxylation, VHL binding, proteasomal degradation of HIF-1alpha, and inhibition of HIF-1-mediated transcription. OS-9 loss-of-function caused by RNA interference increases HIF-1alpha protein levels, HIF-1-mediated transcription, and VEGF mRNA expression under nonhypoxic conditions. These data indicate that OS-9 is an essential component of a multiprotein complex that regulates HIF-1alpha levels in an O-2-dependent manner.