Ubiquitination-Deficient Mutations in Human Piwi Cause Male Infertility by Impairing Histone-to-Protamine Exchange during Spermiogenesis.
Ubiquitination-Deficient Mutations in Human Piwi Cause Male Infertility by Impairing Histone-to-Protamine Exchange during Spermiogenesis.
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DOI：
10.1016/j.cell.2017.04.034
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发表时间：
2017-06-01
期刊：
影响因子：
64.5
通讯作者：
Liu MF
中科院分区：
文献类型：
--
作者：
Gou LT;Kang JY;Dai P;Wang X;Li F;Zhao S;Zhang M;Hua MM;Lu Y;Zhu Y;Li Z;Chen H;Wu LG;Li D;Fu XD;Li J;Shi HJ;Liu MF
遗传学研究已经阐明了Piwi蛋白在动物生殖系发育中的关键作用，但Piwi是否是人类不育症的实际疾病基因仍不清楚。我们报告了无精子症患者中人类Piwi（Hiwi）的生殖系突变，该突变阻止了其泛素化和降解。通过在Piwi（Miwi）基因敲入小鼠中模拟这种突变，我们证明了遗传缺陷是导致男性不育的直接原因。从机制上讲，我们表明，MIWI结合组蛋白泛素连接酶RNF 8的Piwi相互作用的RNA（皮尔纳）的独立方式，和MIWI稳定隔离RNF 8在细胞质中的晚期精子细胞。所得的异常精子显示组蛋白保留、异常形态和严重受损的活性，其可以通过用RNF 8-N肽阻断精子细胞中的RNF 8-MIWI相互作用而在功能上被拯救。总的来说，我们的研究结果确定Piwi作为一个因素，在人类不育症，并揭示其在调节组蛋白，鱼精蛋白交换精子发生过程中的作用。小鼠和人类的雄性不育症可能是由稳定晚期精子细胞中Piwi蛋白的突变引起的：精子缺陷是由于异常的组蛋白保留，而不是皮尔纳失调。
Genetic studies have elucidated critical roles of Piwi proteins in germline development in animals, but whether Piwi is an actual disease gene in human infertility remains unknown. We report germline mutations in human Piwi (Hiwi) in patients with azoospermia that prevent its ubiquitination and degradation. By modeling such mutations in Piwi (Miwi) knockin mice, we demonstrate that the genetic defects are directly responsible for male infertility. Mechanistically, we show that MIWI binds the histone ubiquitin ligase RNF8 in a Piwi-interacting RNA (piRNA)-independent manner, and MIWI stabilization sequesters RNF8 in the cytoplasm of late spermatids. The resulting aberrant sperm show histone retention, abnormal morphology, and severely compromised activity, which can be functionally rescued via blocking RNF8-MIWI interaction in spermatids with an RNF8-N peptide. Collectively, our findings identify Piwi as a factor in human infertility and reveal its role in regulating the histone-to-protamine exchange during spermiogenesis. Male infertility in mice and humans can result from mutations that stabilize the Piwi protein in late spermatids: sperm defects are due to aberrant histone retention, not piRNA misregulation.
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