Department of Pathology and Laboratory Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania 19104.
Department of Pathology and Laboratory Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania 19104.
J Biol Chem. 2013 Apr 5;288(14):9662-9674. doi: 10.1074/jbc.M112.440552. Epub 2013 Feb 14.
Prolyl hydroxylase domain protein 2 (PHD2, also known as Egg Laying Defective Nine homolog 1) is a key oxygen-sensing protein in metazoans. In an oxygen-dependent manner, PHD2 site-specifically prolyl hydroxylates the master transcription factor of the hypoxic response, hypoxia-inducible factor-α (HIF-α), thereby targeting HIF-α for degradation. In this report we show that the heat shock protein 90 (HSP90) co-chaperones p23 and FKBP38 interact via a conserved Pro-Xaa-Leu-Glu motif (where Xaa = any amino acid) in these proteins with the N-terminal Myeloid Nervy and DEAF-1 (MYND)-type zinc finger of PHD2. Knockdown of p23 augments hypoxia-induced HIF-1α protein levels and HIF target genes. We propose that p23 recruits PHD2 to the HSP90 machinery to facilitate HIF-1α hydroxylation. These findings identify a link between two ancient pathways, the PHD:HIF and the HSP90 pathways, and suggest that this link was established concurrent with the emergence of the PHD:HIF pathway in evolution.
脯氨酰羟化酶结构域蛋白 2（PHD2，也称为卵母细胞排放缺陷 9 同源物 1）是后生动物中关键的氧感应蛋白。在依赖氧的方式中，PHD2 特异性脯氨酰羟化缺氧反应的主转录因子缺氧诱导因子-α（HIF-α），从而靶向 HIF-α进行降解。在本报告中，我们表明热休克蛋白 90（HSP90）共伴侣 p23 和 FKBP38 通过这些蛋白质中的保守 Pro-Xaa-Leu-Glu 基序（其中 Xaa = 任何氨基酸）与 PHD2 的 N 端髓样神经和 DEAF-1（MYND）型锌指相互作用。p23 的敲低会增加低氧诱导的 HIF-1α 蛋白水平和 HIF 靶基因。我们提出 p23 将 PHD2 募集到 HSP90 机器中，以促进 HIF-1α 的羟化。这些发现将 PHD:HIF 和 HSP90 途径这两个古老的途径联系起来，并表明这种联系是在 PHD:HIF 途径在进化中出现时建立的。
