TET is targeted for proteasomal degradation by the PHD-pVHL pathway to reduce DNA hydroxymethylation
TET is targeted for proteasomal degradation by the PHD-pVHL pathway to reduce DNA hydroxymethylation
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TET 通过 PHD-pVHL 途径进行蛋白酶体降解，以减少 DNA 羟甲基化。
DOI：
10.1074/jbc.ra120.014538
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发表时间：
2020-11-27
影响因子：
4.8
通讯作者：
Xiao, Wuhan
中科院分区：
文献类型：
--
作者：
Fan, Sijia;Wang, Jing;Xiao, Wuhan
低氧诱导因子是异源二聚体转录因子，在细胞适应低氧的能力中起关键作用。von Hippel-Lindau肿瘤抑制因子（pVHL）是HIF活性的主要调节因子，其靶向脯氨酰羟基化HIF-α在常氧条件下的蛋白酶体降解被认为是pVHL肿瘤抑制和细胞对氧反应的主要机制。pVHL是否通过类似的机制调节其他靶标在很大程度上是未知的。在这里，我们确定TET 2/3作为pVHL的新靶点。pVHL诱导TET 2/3的蛋白酶体降解，导致总体5-羟甲基胞嘧啶水平降低。这两种蛋白质的cAMP/LAP样基序内的保守脯氨酸残基被脯氨酰羟化酶（PHD 2/EGLN 1和PHD 3/EGLN 3）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，egln 1a/b-双-null和egln 3-null胚胎中5-羟甲基胞嘧啶水平的整体增强。因此，我们揭示了PHD-pVHL途径在调节泰特蛋白稳定性和活性中的新功能。这些数据扩展了我们对泰特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。
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-alpha 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.