A Feedback Loop Involving the Phd3 Prolyl Hydroxylase Tunes the Mammalian Hypoxic Response In Vivo
A Feedback Loop Involving the Phd3 Prolyl Hydroxylase Tunes the Mammalian Hypoxic Response In Vivo
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DOI：
10.1128/mcb.00331-09
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发表时间：
2009-11-01
影响因子：
5.3
通讯作者：
Kaelin, William G., Jr.
中科院分区：
文献类型：
--
作者：
Minamishima, Yoji Andrew;Moslehi, Javid;Kaelin, William G., Jr.
低氧诱导因子（Hypoxia-inducible factor，HIF）是低氧应答基因的主要调节因子，由一个不稳定的α亚基和一个稳定的β亚基组成。HIF α经历氧依赖性脯氨酰羟基化，这标志着它被含有von Hippel-Lindau蛋白（pVHL）的复合物多泛素化。在三个Phd家族成员中，Phd 2似乎是主要的HIF脯氨酰羟化酶。Phd 3由HIF诱导，并且基于体外研究的发现，可能参与HIF调节反馈回路。在这里，我们报告说，Phd 3的损失加剧了HIF激活，肝脂肪变性，扩张型心肌病，并在缺乏Phd 2单独的小鼠中观察到的过早死亡，并产生更密切的phenocopy的变化，在缺乏pVHL的小鼠比Phd 2单独的损失。重要的是，Phd 3可以补偿Phd 2损失的程度以及Phd 2和Phd 3的组合损失类似于pVHL损失的程度对于不同的HIF应答基因和不同的组织似乎是不同的。这些研究结果强调，不同的HIF靶基因的脯氨酰羟化酶活性的变化的反应不同，定量和定性，在体内和paralog-specific脯氨酰羟化酶抑制剂作为治疗剂的发展具有影响。
Hypoxia-inducible factor (HIF), consisting of a labile alpha subunit and a stable beta subunit, is a master regulator of hypoxia-responsive mRNAs. HIF alpha undergoes oxygen-dependent prolyl hydroxylation, which marks it for polyubiquitination by a complex containing the von Hippel-Lindau protein (pVHL). Among the three Phd family members, Phd2 appears to be the primary HIF prolyl hydroxylase. Phd3 is induced by HIF and, based on findings from in vitro studies, may participate in a HIF-regulatory feedback loop. Here, we report that Phd3 loss exacerbates the HIF activation, hepatic steatosis, dilated cardiomyopathy, and premature mortality observed in mice lacking Phd2 alone and produces a closer phenocopy of the changes seen in mice lacking pVHL than the loss of Phd2 alone. Importantly, the degree to which Phd3 can compensate for Phd2 loss and the degree to which the combined loss of Phd2 and Phd3 resembles pVHL loss appear to differ for different HIF-responsive genes and in different tissues. These findings highlight that the responses of different HIF target genes to changes in prolyl hydroxylase activity differ, quantitatively and qualitatively, in vivo and have implications for the development of paralog-specific prolyl hydroxylase inhibitors as therapeutic agents.