Siah2 regulates stability of prolyl-hydroxylases, controls HIF1α abundance, and modulates physiological responses to hypoxia
Siah2 regulates stability of prolyl-hydroxylases, controls HIF1α abundance, and modulates physiological responses to hypoxia
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DOI：
10.1016/j.cell.2004.06.001
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发表时间：
2004-06-25
期刊：
影响因子：
64.5
通讯作者：
Ronai, Z
中科院分区：
文献类型：
--
作者：
Nakayama, K;Frew, IJ;Ronai, Z
缺氧诱导因子-1 α（HIF 1 α）是细胞对缺氧反应的中心调节因子。PHD酶对HIF 1 α的脯氨酰羟基化是HIF 1 α降解的先决条件。在这里，我们证明了PHD 1和PHD 3的丰度通过其靶向蛋白酶体依赖性降解的E3泛素连接酶Siah 1a/2，在缺氧条件下进行调节。Siah 2 null成纤维细胞表现出延长的PHD 3半衰期，导致缺氧期间HIF 1 α表达水平降低。值得注意的是，缺氧诱导的HIF 1 α表达在Siah 1a/2 null细胞中被完全抑制，但可以通过RNAi抑制PHD 3来拯救。Siah 2靶向PHD 3降解在暴露于甚至温和的缺氧条件后增加，这与Siah 2转录增加一致。Siah 2基因敲除小鼠缺氧表现出呼吸过度反应受损和血红蛋白水平降低。因此，Siah 1a/2对PHD 1/3的控制构成了缺氧期间HIF 1 α调节的另一个复杂性水平。
Hypoxia-inducible factor-1alpha (HIF1alpha) is a central regulator of the cellular response to hypoxia. Prolyl-hydroxylation of HIF1alpha by PHD enzymes is prerequisite for HIF1alpha degradation. Here, we demonstrate that the abundance of PHD1 and PHD3 are regulated via their targeting for proteasome-dependent degradation by the E3 ubiquitin ligases Siah1a/2, under hypoxia conditions. Siah2 null fibroblasts exhibit prolonged PHD3 half-life, resulting in lower levels of HIF1alpha expression during hypoxia. Significantly, hypoxia-induced HIF1alpha expression was completely inhibited in Siah1a/2 null cells, yet could be rescued upon inhibition of PHD3 by RNAi. Siah2 targeting of PHD3 for degradation increases upon exposure to even mild hypoxic conditions, which coincides with increased Siah2 transcription. Siah2 null mice subjected to hypoxia displayed an impaired hyperpneic respiratory response and reduced levels of hemoglobin. Thus, the control of PHD1/3 by Siah1a/2 constitutes another level of complexity in the regulation of HIF1alpha during hypoxia.