a Center for Reproductive Medicine, Department of Obstetrics and Gynecology , Peking University Third Hospital , Beijing , China.
b Key Laboratory of Assisted Reproduction , Ministry of Education , Beijing , China.
Cell Cycle. 2019 Jun;18(11):1254-1267. doi: 10.1080/15384101.2019.1617453. Epub 2019 May 21.
Mammalian oocyte meiosis is a special form of cell division that provides haploid gametes for fertilization. Unlike in mitosis, post-translational modifications (PTMs) are more crucial during meiosis because of the absence of de novo mRNA transcription. As a classic PTM, protein neddylation is a biological process that mediates protein degradation by modifying cullin proteins and activating the Cullin-Ring E3 ligases. This process plays important roles in various biological processes such as autophagy and tumorigenesis. However, the function of neddylation in germ cells is unknown. In this study, we observed that the inhibition of neddylation by its specific inhibitor MLN4924 significantly arrests mouse oocyte at the stage of metaphase during meiosis. The arrested oocytes display impaired spindles with over-activation of spindle assembly checkpoint (SAC). Accordingly, we identified early mitosis inhibitor 1 (Emi1), a key inhibitor of anaphase-promoting complex/cyclosome (APC/C), as a substrate of neddylation-mediated protein degradation. Thus, our study uncovered an unknown role of neddylation in female germ cells and suggests that proper neddylation is essential for oocyte maturation.
哺乳动物卵母细胞减数分裂是一种特殊的细胞分裂形式，为受精提供单倍体配子。与有丝分裂不同，由于没有新的 mRNA 转录，翻译后修饰 (PTMs) 在减数分裂中更为重要。作为一种经典的 PTM，蛋白质 neddylation 是一种通过修饰 cullin 蛋白并激活 Cullin-Ring E3 连接酶来介导蛋白质降解的生物过程。这个过程在自噬和肿瘤发生等各种生物过程中发挥着重要作用。然而，neddylation 在生殖细胞中的功能尚不清楚。在这项研究中，我们观察到其特异性抑制剂 MLN4924 的抑制作用显著将小鼠卵母细胞阻滞在减数分裂中期。被阻滞的卵母细胞显示出纺锤体受损，纺锤体组装检查点 (SAC) 过度激活。因此，我们鉴定出早期有丝分裂抑制剂 1 (Emi1)，一种后期促进复合物/环体 (APC/C) 的关键抑制剂，作为 neddylation 介导的蛋白降解的底物。因此，我们的研究揭示了 neddylation 在雌性生殖细胞中的未知作用，并表明适当的 neddylation对于卵母细胞成熟是必不可少的。
