Regulation of adult erythropoiesis by prolyl hydroxylase domain proteins
Regulation of adult erythropoiesis by prolyl hydroxylase domain proteins
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DOI：
10.1182/blood-2007-09-114561
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发表时间：
2008-03-15
期刊：
影响因子：
20.3
通讯作者：
Fong, Guo-Hua
中科院分区：
文献类型：
--
作者：
Takeda, Kotaro;Aguila, Hector L.;Fong, Guo-Hua
红细胞增多症通常与促红细胞生成素 (EPO) 过度表达和氧感应缺陷有关。在正常细胞中，细胞内氧浓度由含有脯氨酰羟化酶结构域 (PHD) 的蛋白质直接感知，这些蛋白质标记缺氧诱导因子 (HIF) α 亚基，通过氧依赖性脯氨酰羟化进行多泛素化和蛋白酶体降解。在这里，我们发现不同的 PHD 亚型差异调节成人肝脏和肾脏中的 HIF-α 稳定性，并通过不同的机制抑制 Epo 表达和红细胞生成。尽管Phd1(-/-)或Phd3(-/-)小鼠没有明显的缺陷，但Phd1和Phd3的双敲除导致中度红细胞增多。 HIF-2 α 已知可激活 Epo 表达，并在肝脏中积聚。在缺乏 PHD2 的成年小鼠中，原型 Epo 转录激活剂 HIF-1 α 在肾脏和肝脏中积累。 HIF-1α水平升高与肾脏中的Epo mRNA和血清中的Epo蛋白浓度显着升高相关，从而导致严重的红细胞增多。相比之下，Phd2 的杂合突变对血液稳态没有可检测到的影响。这些发现表明，PHD1/3双重缺陷部分通过激活肝脏HIF-2α/Epo途径导致红细胞增多，而PHD2缺陷通过激活肾脏Epo途径导致红细胞增多。
Polycythemia is often associated with erythropoietin (EPO) overexpression and defective oxygen sensing. In normal cells, intracellular oxygen concentrations are directly sensed by prolyl hydroxylase domain (PHD)-containing proteins, which tag hypoxia-inducible factor (HIF) alpha subunits for polyubiquitination and proteasomal degradation by oxygen-dependent prolyl hydroxylation. Here we show that different PHD isoforms differentially regulate HIF-alpha stability in the adult liver and kidney and suppress Epo expression and erythropoiesis through distinct mechanisms. Although Phd1(-/-) or Phd3(-/-) mice had no apparent defects, double knockout of Phd1 and Phd3 led to moderate erythrocytosis. HIF-2 alpha, which is known to activate Epo expression, accumulated in the liver. In adult mice deficient for PHD2, the prototypic Epo transcriptional activator HIF-1 alpha accumulated in both the kidney and liver. Elevated HIF-1 alpha levels were associated with dramatically increased concentrations of both Epo mRNA in the kidney and Epo protein in the serum, which led to severe erythrocytosis. In contrast, heterozygous mutation of Phd2 had no detectable effects on blood homeostasis. These findings suggest that PHD1/3 double deficiency leads to erythrocytosis partly by activating the hepatic HIF-2 alpha/Epo pathway, whereas PHD2 deficiency leads to erythrocytosis by activating the renal Epo pathway.