Targeting of HIF-α to the von Hippel-Lindau ubiquitylation complex by O2-regulated prolyl hydroxylation
Targeting of HIF-α to the von Hippel-Lindau ubiquitylation complex by O2-regulated prolyl hydroxylation
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DOI：
10.1126/science.1059796
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发表时间：
2001-04-20
期刊：
影响因子：
56.9
通讯作者：
Ratcliffe, PJ
中科院分区：
文献类型：
--
作者：
Jaakkola, P;Mole, DR;Ratcliffe, PJ
缺氧诱导因子（HIF）是一种转录复合物，在氧对基因表达的调控中起着重要作用。在含氧和铁充足的细胞中，HIF-alpha亚基通过涉及von Hippel-Lindau肿瘤抑制因子（pVHL）E3连接酶复合物遍在化的机制迅速被破坏。这一过程被缺氧和铁螯合抑制，从而允许转录激活。在这里，我们表明，人pVHL和HIF-1 α亚基的特定结构域之间的相互作用是通过羟化脯氨酸残基（HIF-1 α P564）的酶，我们称之为HIF-α脯氨酰羟化酶（HIF-PH）进行调节。对分子氧作为辅助底物和铁作为辅助因子的绝对要求表明HIF-PH直接作为细胞氧传感器起作用。
Hypoxia-inducible factor (HIF) is a transcriptional complex that plays a central role in the regulation of gene expression by oxygen. In oxygenated and iron replete cells, HIF-alpha subunits are rapidly destroyed by a mechanism that involves ubiquitylation by the von Hippel-Lindau tumor suppressor (pVHL) E3 Ligase complex. This process is suppressed by hypoxia and iron chelation, allowing transcriptional activation. Here we show that the interaction between human pVHL and a specific domain of the HIF-1 alpha subunit is regulated through hydroxylation of a proline residue (HIF-1 alpha P564) by an enzyme we have termed HIF-alpha prolyl-hydroxylase (HIF-PH). An absolute requirement for dioxygen as a cosubstrate and iron as cofactor suggests that HIF-PH functions directly as a cellular oxygen sensor.