MDM2 E3 ligase-mediated ubiquitination and degradation of HDAC1 in vascular calcification.
MDM2 E3 ligase-mediated ubiquitination and degradation of HDAC1 in vascular calcification.
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MDM2 E3连接酶介导的HDAC1在血管钙化中的泛素化和降解。
DOI：
10.1038/ncomms10492
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发表时间：
2016-02-01
影响因子：
16.6
通讯作者：
Kook H
中科院分区：
文献类型：
--
作者：
Kwon DH;Eom GH;Ko JH;Shin S;Joung H;Choe N;Nam YS;Min HK;Kook T;Yoon S;Kang W;Kim YS;Kim HS;Choi H;Koh JT;Kim N;Ahn Y;Cho HJ;Lee IK;Park DH;Suk K;Seo SB;Wissing ER;Mendrysa SM;Nam KI;Kook H
血管钙化（VC）通常与心血管和代谢疾病相关。然而，VC 与这些疾病的分子机制尚未阐明。在这里，我们报道 MDM2 诱导的组蛋白脱乙酰酶 1 (HDAC1) 泛素化介导 VC。通过化学抑制剂或基因消融导致 HDAC1 活性丧失会增强 VC。在细胞和动物钙化模型以及人类钙化冠状动脉中，HDAC1 蛋白（而非 mRNA）减少。在钙化诱导条件下，HDAC1 的蛋白酶体降解先于 VC，并且由启动 HDAC1 K74 泛素化的 MDM2 E3 泛素连接酶介导。 MDM2 的过度表达会增强 VC，而 MDM2 的缺失则会减弱它。跨越 HDAC1 K74 和 RG 7112（一种 MDM2 抑制剂）的诱饵肽可在体内和体外预防 VC。这些结果揭示了一条以前未被重视的泛素化途径，并表明 MDM2 介导的 HDAC1 泛素化可以作为 VC 的新治疗靶点。 血管钙化（VC）会增加心血管和代谢疾病的发病率和死亡率。在这里，Kwon 等人。显示钙化刺激诱导 MDM2 介导的 HDAC1 泛素化和蛋白酶体降解，这表明治疗 VC 患者的可能治疗策略。
Vascular calcification (VC) is often associated with cardiovascular and metabolic diseases. However, the molecular mechanisms linking VC to these diseases have yet to be elucidated. Here we report that MDM2-induced ubiquitination of histone deacetylase 1 (HDAC1) mediates VC. Loss of HDAC1 activity via either chemical inhibitor or genetic ablation enhances VC. HDAC1 protein, but not mRNA, is reduced in cell and animal calcification models and in human calcified coronary artery. Under calcification-inducing conditions, proteasomal degradation of HDAC1 precedes VC and it is mediated by MDM2 E3 ubiquitin ligase that initiates HDAC1 K74 ubiquitination. Overexpression of MDM2 enhances VC, whereas loss of MDM2 blunts it. Decoy peptide spanning HDAC1 K74 and RG 7112, an MDM2 inhibitor, prevent VC in vivo and in vitro. These results uncover a previously unappreciated ubiquitination pathway and suggest MDM2-mediated HDAC1 ubiquitination as a new therapeutic target in VC. Vascular calcification (VC) increases morbidity and mortality in cardiovascular and metabolic diseases. Here, Kwon et al. show that calcification stimuli induce MDM2- mediated ubiquitination and proteasomal degradation of HDAC1, suggesting a possible therapeutic strategy for treatment of VC patients.