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首页> 外文期刊>Molecular and Cellular Biology >Coordinate Regulation of the Oxygen-Dependent Degradation Domains of Hypoxia-Inducible Factor 1α
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Coordinate Regulation of the Oxygen-Dependent Degradation Domains of Hypoxia-Inducible Factor 1α

机译：缺氧诱导因子1α的氧依赖性降解域的协调调控。

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Oxygen-dependent proteolysis is the primary means of regulating the hypoxia-inducible factor (HIF) family of transcription factors. The alpha-subunit of HIF factor 1 (HIF-1) contains two highly conserved oxygen-dependent degradation domains (402 ODD and 564 ODD), each of which includes a proline that is hydroxylated in the presence of oxygen, allowing the von Hippel-Lindau (VHL) E3 ubiquitin ligase to interact and target HIF-1α to the proteasome for degradation. Mutation of either proline is sufficient to partially stabilize HIF-1α under conditions of normoxia, but the specific contributions of each hydroxylation event to the regulation of HIF-1α are unknown. Here we show that the two ODDs of HIF-1α have independent yet interactive roles in the regulation of HIF-1α protein turnover, with the relative involvement of each ODD depending on the levels of oxygen. Using hydroxylation-specific antibodies, we found that under conditions of normoxia proline 564 is hydroxylated prior to proline 402, and mutation of proline 564 results in a significant reduction in the hydroxylation of proline 402. Mutation of proline 402, however, has little effect on the hydroxylation of proline 564. To determine whether the more rapid hydroxylation of the proline 564 under conditions of normoxia is due to a preference for the particular sequence surrounding proline 564 or for that site within the protein, we exchanged the degradation domains within the full-length HIF-1α protein. In these domain-swapping experiments, prolyl hydroxylase domain 1 (PHD1) and PHD2 preferentially hydroxylated the proline located in the site of the original 564 ODD, while PHD3 preferred the proline 564 sequence, regardless of its location. At limiting oxygen tensions, we found that proline 402 exhibits an oxygen-dependent decrease in hydroxylation at higher oxygen tensions relative to proline 564 hydroxylation. These results indicate that hydroxylation of proline 402 is highly responsive to physiologic changes in oxygen and, therefore, plays a more important role in HIF-1α regulation under conditions of hypoxia than under conditions of normoxia. Together, these findings demonstrate that each hydroxylated proline of HIF-1α has a distinct activity in controlling HIF-1α stability in response to different levels of oxygenation.
机译：氧依赖性蛋白水解是调节缺氧诱导因子（HIF）转录因子家族的主要手段。 HIF因子1（HIF-1）的α亚基包含两个高度保守的氧依赖性降解域（402 ODD和564 ODD），每个域都包含一个脯氨酸，脯氨酸在氧气的存在下会被羟基化，从而使von Hippel- Lindau（VHL）E3泛素连接酶相互作用，并将HIF-1α靶向蛋白酶体进行降解。任一脯氨酸的突变足以在常氧条件下部分稳定HIF-1α，但尚不清楚每个羟基化事件对HIF-1α调控的具体作用。在这里，我们显示了HIF-1α的两个ODD在调节HIF-1α蛋白更新中具有独立但相互作用的作用，每个ODD的相对参与取决于氧气的水平。使用羟基化特异性抗体，我们发现在常氧条件下，脯氨酸564在脯氨酸402之前被羟基化，脯氨酸564的突变导致脯氨酸402的羟基化显着减少。然而，脯氨酸402的突变对为了确定在常氧条件下脯氨酸564的更快羟基化是由于偏爱脯氨酸564周围的特定序列还是蛋白质内的该位点而引起的，我们交换了全脂蛋白内的降解域长度的HIF-1α蛋白。在这些域交换实验中， p rolyl h 羟化酶 d omain 1（PHD1）和PHD2优先羟化了位于脯氨酸位点的脯氨酸原始564 ODD，而PHD3优先选择脯氨酸564序列，而不管其位置如何。在极限氧张力下，我们发现脯氨酸402在较高的氧张力下相对于脯氨酸564的羟基化表现出羟基依赖性的羟基依赖性降低。这些结果表明脯氨酸402的羟基化对氧的生理变化具有高度响应性，因此，在缺氧条件下比在正常氧条件下，在HIF-1α调节中起更重要的作用。总之，这些发现表明，HIF-1α的每个羟化脯氨酸在控制HIF-1α稳定性方面具有不同的活性，以响应不同程度的氧合。

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