The deletion of the protein phosphatase 1 regulator NIPP1 in testis causes hyperphosphorylation and degradation of the histone methyltransferase EZH2
The deletion of the protein phosphatase 1 regulator NIPP1 in testis causes hyperphosphorylation and degradation of the histone methyltransferase EZH2
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DOI：
10.1074/jbc.ac118.005577
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发表时间：
2018-11-23
影响因子：
4.8
通讯作者：
Bollen, Mathieu
中科院分区：
文献类型：
--
作者：
Ferreira, Monica;Verbinnen, Iris;Bollen, Mathieu
生殖细胞增殖受表观遗传控制，主要通过 DNA 甲基化和组蛋白修饰。然而，出生后睾丸生殖细胞自我更新和分化的关键表观遗传调节因子仍不清楚。 zeste 同源物 2 (EZH2) 的组蛋白甲基转移酶增强子是 Polycomb 抑制复合物 2 的催化亚基，通过组蛋白 H3 在 Lys-27 (H3K27me3) 上的三甲基化来抑制靶基因，并与蛋白磷酸酶 1 (PP1) 和 PP1 核抑制剂 (NIPP1) 直接相互作用。在这里，我们报告说，小鼠出生后睾丸特异性消融 NIPP1 会导致 EZH2 丢失并降低 H3K27me3 水平。从机制上讲，NIPP1 缺失消除了 PP1 介导的 EZH2 在两个细胞周期蛋白依赖性激酶位点 (Thr-345/487) 去磷酸化，从而产生过度磷酸化的 EZH2，这是蛋白水解降解的底物。因此，这些残基的丙氨酸突变延长了EZH2在雄性生殖细胞中的半衰期。我们的研究揭示了 PP1:NIPP1 全酶在稳定 EZH2 和维持对生殖细胞发育和精子发生很重要的基因上的 H3K27me3 标记方面的关键作用。
Germ cell proliferation is epigenetically controlled, mainly through DNA methylation and histone modifications. However, the pivotal epigenetic regulators of germ cell self-renewal and differentiation in postnatal testis are still poorly defined. The histone methyltransferase enhancer of zeste homolog 2 (EZH2) is the catalytic subunit of Polycomb repressive complex 2, represses target genes through trimethylation of histone H3 at Lys-27 (H3K27me3), and interacts (in)directly with both protein phosphatase 1 (PP1) and nuclear inhibitor of PP1 (NIPP1). Here, we report that postnatal, testis-specific ablation of NIPP1 in mice results in loss of EZH2 and reduces H3K27me3 levels. Mechanistically, the NIPP1 deletion abrogated PP1-mediated EZH2 dephosphorylation at two cyclin-dependent kinase sites (Thr-345/487), thereby generating hyperphosphorylated EZH2, which is a substrate for proteolytic degradation. Accordingly, alanine mutation of these residues prolonged the half-life of EZH2 in male germ cells. Our study discloses a key role for the PP1:NIPP1 holoenzyme in stabilizing EZH2 and maintaining the H3K27me3 mark on genes that are important for germ cell development and spermatogenesis.