Hypoxia-inducible factors are heterodimeric transcription factors that play a crucial role in a cell's ability to adapt to low oxygen. The von Hippel-Lindau tumor suppressor (pVHL) acts as a master regulator of HIF activity, and its targeting of prolyl hydroxylated HIF-α for proteasomal degradation under normoxia is thought to be a major mechanism for pVHL tumor suppression and cellular response to oxygen. Whether pVHL regulates other targets through a similar mechanism is largely unknown. Here, we identify TET2/3 as novel targets of pVHL. pVHL induces proteasomal degradation of TET2/3, resulting in reduced global 5-hydroxymethylcytosine levels. Conserved proline residues within the LAP/LAP-like motifs of these two proteins are hydroxylated by the prolyl hydroxylase enzymes (PHD2/EGLN1 and PHD3/EGLN3), which is prerequisite for pVHL-mediated degradation. Using zebrafish as a model, we determined that global 5-hydroxymethylcytosine levels are enhanced in vhl-null, egln1a/b-double-null, and egln3-null embryos. Therefore, we reveal a novel function for the PHD-pVHL pathway in regulating TET protein stability and activity. These data extend our understanding of how TET proteins are regulated and provide new insight into the mechanisms of pVHL in tumor suppression.

中文翻译：

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TET 通过 PHD-pVHL 途径靶向蛋白酶体降解，以减少 DNA 羟甲基化。

缺氧诱导因子是异二聚体转录因子，在细胞适应低氧的能力中起着至关重要的作用。von Hippel-Lindau 肿瘤抑制因子 (pVHL) 作为 HIF 活性的主要调节因子，其靶向脯氨酰羟基化 HIF-α 以在常氧条件下进行蛋白酶体降解被认为是 pVHL 肿瘤抑制和细胞对氧气的反应的主要机制。pVHL 是否通过类似的机制调节其他目标在很大程度上是未知的。在这里，我们将 TET2/3 确定为 pVHL 的新靶点。pVHL 诱导 TET2/3 的蛋白酶体降解，导致整体 5-羟甲基胞嘧啶水平降低。这两种蛋白质的 LAP/LAP 样基序中的保守脯氨酸残基被脯氨酰羟化酶（PHD2/EGLN1 和 PHD3/EGLN3）羟基化，这是 pVHL 介导的降解的先决条件。使用斑马鱼作为模型，我们确定了 vhl-null、egln1a/b-double-null 和 egln3-null 胚胎中的全局 5-羟甲基胞嘧啶水平增强。因此，我们揭示了 PHD-pVHL 通路在调节 TET 蛋白稳定性和活性方面的新功能。这些数据扩展了我们对 TET 蛋白如何调节的理解，并为 pVHL 在肿瘤抑制中的机制提供了新的见解。