PHDs overactivation during chronic hypoxia "desensitizes" HIFα and protects cells from necrosis
PHDs overactivation during chronic hypoxia "desensitizes" HIFα and protects cells from necrosis
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DOI：
10.1073/pnas.0705680105
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发表时间：
2008-03-25
影响因子：
11.1
通讯作者：
Berra, Edurne
中科院分区：
文献类型：
--
作者：
Ginouves, Amandine;Ilc, Karine;Berra, Edurne
细胞对氧（O-2）可用性变化的适应由O-2依赖性酶的两个亚家族控制：缺氧诱导因子（HIF）-脯氨酰和天冬酰胺酰羟化酶[脯氨酰羟化酶结构域（PHDs）和抑制HIF的因子（FIH）]。这些氧传感器调节HIF的活性，HIF是O-2稳态的转录复合物。在氧合良好的细胞中，PHD使HIF α亚基羟基化，从而靶向它们进行蛋白酶体降解。相反，急性缺氧抑制PHDs，导致HIF α稳定。然而，在这里，我们表明，慢性缺氧诱导HIF 1/2 α的“脱敏”在cellulo和小鼠。在这个一般的适应机制的基础上，我们证明，慢性缺氧不仅增加了池的PHDs，但也过度激活的三个PHD亚型。这种过度激活似乎是介导的细胞内的O-2的可用性随之抑制线粒体呼吸的增加。通过在细胞内和体内使用siRNA，我们发现PHD是触发HIF α脱敏的关键酶，HIF α脱敏是保护细胞免受坏死细胞死亡并因此使其适应慢性缺氧所需的反馈机制。因此，PHD作为双酶，其失活和随后的过度活化分别是细胞在急性或慢性缺氧中存活所必需的。
Cell adaptation to changes in oxygen (O-2) availability is controlled by two subfamilies of O-2-dependent enzymes: the hypoxia inducible factor (HIF)-prolyl and asparaginyl hydroxylases [prolyl hydroxylases domain (PHDs) and factor inhibiting HIF (FIH)]. These oxygen sensors regulate the activity of the HIF, a transcriptional complex central in O-2 homeostasis. in well oxygenated cells, PHDs hydroxylate the HIF alpha subunits, thereby targeting them for proteasomal degradation. In contrast, acute hypoxia inhibits PHDs, leading to HIF alpha stabilisation. However, here we show that chronic hypoxia induces HIF1/2 alpha"desensitization" in cellulo and in mice. At the basis of this general adaptative mechanism, we demonstrate that chronic hypoxia not only increases the pool of PHDs but also overactivates the three PHD isoforms. This overactivation appears to be mediated by an increase in intracellular O-2 availability consequent to the inhibition of mitochondrial respiration. By using in cellulo and in vivo siRNA, we found that the PHDs are the key enzymes triggering HIFa desensitization, a feedback mechanism required to protect cells against necrotic cell death and thus to adapt them across a chronic hypoxia. Hence, PHDs serve as dual enzymes, for which inactivation and later overactivation is necessary for cell survival in acute or chronic hypoxia, respectively.