Deubiquitylase USP7 regulates human terminal erythroid differentiation by stabilizing GATA1
Deubiquitylase USP7 regulates human terminal erythroid differentiation by stabilizing GATA1
复制标题
去泛素化酶 USP7 通过稳定 GATA1 调节人终末红细胞分化
DOI：
10.3324/haematol.2018.206227
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发表时间：
2019-10-30
期刊：
影响因子：
10.1
通讯作者：
Liu, Jing
中科院分区：
文献类型：
--
作者：
Liang, Long;Peng, Yuanliang;Liu, Jing
泛素化是影响蛋白质命运的酶促翻译后修饰。泛素-蛋白酶体系统（UPS）首先在网织红细胞中发现，在网织红细胞成熟中起重要作用。最近的研究表明，泛素化是一个动态的、可逆的过程，去泛素化酶能够将泛素从其蛋白质底物上去除。鉴于UPS在网织红细胞中高度活跃的事实，推测去泛素化酶可能在红细胞生成中起重要作用。然而，去泛素化酶在红细胞生成中的作用仍然在很大程度上未被探索。在本研究中，我们发现去泛素化酶USP 7的表达显着增加，在人类终末红系分化。我们进一步表明，通过短发夹RNA介导的敲低或USP 7特异性抑制剂干扰USP 7功能，由于GATA 1水平降低而损害人终末红细胞分化，并且GATA 1水平的恢复挽救了分化缺陷。从机制上讲，USP 7缺陷导致GATA 1蛋白水平降低，可通过蛋白酶体抑制剂逆转。此外，USP 7直接与GATA 1相互作用，并催化去除结合到GATA 1上的K48连接的聚泛素化链，从而稳定GATA 1蛋白。总的来说，我们的研究结果已经确定了一个重要的作用，去泛素化酶在人类终末红细胞分化的稳定GATA 1，红细胞生成的主调节。
Ubiquitination is an enzymatic post-translational modification that affects protein fate. The ubiquitin-proteasome system (UPS) was first discovered in reticulocytes where it plays important roles in reticulocyte maturation. Recent studies have revealed that ubiquitination is a dynamic and reversible process and that deubiquitylases are capable of removing ubiquitin from their protein substrates. Given the fact that the UPS is highly active in reticulocytes, it is speculated that deubiquitylases may play important roles in erythropoiesis. Yet, the role of deubiquitylases in erythropoiesis remains largely unexplored. In the present study, we found that the expression of deubiquitylase USP7 is significantly increased during human terminal erythroid differentiation. We further showed that interfering with USP7 function, either by short hairpin RNA-mediated knockdown or USP7-specific inhibitors, impaired human terminal erythroid differentiation due to decreased GATA1 level and that restoration of GATA1 levels rescued the differentiation defect. Mechanistically, USP7 deficiency led to a decreased GATA1 protein level that could be reversed by proteasome inhibitors. Furthermore, USP7 interacts directly with GATA1 and catalyzes the removal of K48-linked poly ubiquitylation chains conjugated onto GATA1, thereby stabilizing GATA1 protein. Collectively, our findings have identified an important role of a deubiquitylase in human terminal erythroid differentiation by stabilizing GATA1, the master regulator of erythropoiesis.