Activation of the HIF prolyl hydroxylase by the iron chaperones PCBP1 and PCBP2.
Activation of the HIF prolyl hydroxylase by the iron chaperones PCBP1 and PCBP2.
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DOI：
10.1016/j.cmet.2011.08.015
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发表时间：
2011-11-02
期刊：
影响因子：
29
通讯作者：
Philpott CC
中科院分区：
文献类型：
--
作者：
Nandal A;Ruiz JC;Subramanian P;Ghimire-Rijal S;Sinnamon RA;Stemmler TL;Bruick RK;Philpott CC
哺乳动物细胞表达数十种含铁蛋白，但对金属配体掺入的机制知之甚少。人聚（rC）结合蛋白1（PCBP 1）是一种铁分子伴侣，其结合铁并将其递送至铁蛋白（一种胞质铁储存蛋白）。我们已经确定了铁依赖性脯氨酰羟化酶（PHDs）和天冬酰胺酰羟化酶（FIH 1），修饰缺氧诱导因子α（HIFα）作为PCBP 1的靶点。细胞中PCBP 1或PCBP 2的消耗导致PHD活性丧失，表现为HIF 1 α的脯氨酰羟基化减少、HIF 1 α通过VHL/蛋白酶体途径的降解受损以及活性HIF 1转录因子的蓄积。通过添加过量的Fe（II）或纯化的Fe-PCBP 1在体外恢复PHD活性，并且PCBP 1在体内结合到PHD 2和FIH 1。这些数据表明，PCBP 1所需的铁纳入PHD和建议广泛的作用PCBP 1和2在提供铁细胞质非血红素铁酶。
Mammalian cells express dozens of iron-containing proteins, yet little is known about the mechanism of metal ligand incorporation. Human poly (rC) binding protein 1 (PCBP1) is an iron chaperone that binds iron and delivers it to ferritin, a cytosolic iron storage protein. We have identified the iron-dependent prolyl hydroxylases (PHDs) and asparaginyl hydroxylase (FIH1) that modify hypoxia-inducible factor α (HIFα) as targets of PCBP1. Depletion of PCBP1 or PCBP2 in cells led to loss of PHD activity, manifested by reduced prolyl hydroxylation of HIF1α, impaired degradation of HIF1α through the VHL/proteasome pathway, and accumulation of active HIF1 transcription factor. PHD activity was restored in vitro by addition of excess Fe(II), or purified Fe-PCBP1, and PCBP1 bound to PHD2 and FIH1 in vivo. These data indicated that PCBP1 was required for iron incorporation into PHD and suggest a broad role for PCBP1 and 2 in delivering iron to cytosolic nonheme iron enzymes.
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