中科院上海生命科學(xué)學(xué)院的劉默芳（Mo-Fang Liu）研究員和王恩多（En-Duo Wang）院士為這篇論文的共同通訊作者。前者的研究方向是非編碼RNA在癌癥發(fā)生和精子發(fā)生中的功能機制。后者主要從事蛋白質(zhì)生物合成的質(zhì)量控制研究。

    生殖系細(xì)胞擔(dān)負(fù)著遺傳信息的世代傳遞，其基因組的完整性對個體和物種維持都至關(guān)重要。真核生物基因組中存在不少自私的DNA鏈——轉(zhuǎn)座子。這類遺傳物質(zhì)能夠在染色體的不同位點間跳躍，導(dǎo)致基因組不穩(wěn)定，甚至引發(fā)癌癥，在生殖細(xì)胞系中，轉(zhuǎn)座子的跳躍則可能導(dǎo)致不育。

    Piwi互作RNA(piRNA)是近年來新發(fā)現(xiàn)的一類小RNA分子，主要在生殖細(xì)胞系中表達(dá)，對于維持生殖系DNA完整、抑制轉(zhuǎn)座子轉(zhuǎn)錄、抑制翻譯、參與異染色質(zhì)的形成、執(zhí)行表觀遺傳調(diào)控和生殖細(xì)胞發(fā)生等均有重要作用。過去的研究表明，生殖細(xì)胞特異性表達(dá)的PIWI家族蛋白是piRNA作用途徑的中心，為piRNA生物生成及功能所必需。小鼠PIWI家族包括MILI、MIWI和MIWI2三個成員，特異性地在睪丸中表達(dá)，對小鼠精子發(fā)生至關(guān)重要。盡管近來的研究增進(jìn)了我們對于piRNA生物合成及功能的了解，然而其作用通路機制仍然有待深究。

    在這篇文章中，研究人員證實小鼠PIWI (MIWI)是通過APC/C-26S蛋白酶體信號通路進(jìn)行降解，piRNAs通過促進(jìn)MIWI與一種APC/C底物結(jié)合亞基的互作在這一過程中發(fā)揮了至關(guān)重要的作用。有趣的是，研究人員發(fā)現(xiàn)在晚期精細(xì)胞中piRNA觸發(fā)的MIWI破壞，轉(zhuǎn)而導(dǎo)致了piRNA消除，這揭示了一條在特定的發(fā)育階段調(diào)節(jié)性清除MIWI/piRNA機器的前饋機制。重要的是，研究人員發(fā)現(xiàn)適當(dāng)清除MIWI/piRNA是精子成熟的必要條件。

    這些結(jié)果表明piRNAs通過泛素-蛋白酶體信號通路調(diào)控了MIWI/piRNA機器的清除，證實在雄性生殖細(xì)胞發(fā)育過程中適當(dāng)?shù)臅r序調(diào)控MIWI/piRNA具有非常重要的意義。

    piRNA-Triggered MIWI Ubiquitination and Removal by APC/C in Late Spermatogenesis

    Shuang Zhao, Lan-Tao Gou, Man Zhang, Li-Dong Zu, Min-Min Hua, Ye Hua, Hui-Juan Shi, Yong Li, Jinsong Li, Dangsheng Li, En-Duo Wang, Mo-Fang Liu

    The PIWI/PIWI-interacting RNA (piRNA) machinery has been well documented to maintain genome integrity by silencing transposons in animal germ cells. Recent studies have advanced our understanding of the biogenesis and function of this machinery; however, its metabolism has remained largely unexplored. Here, we show that murine PIWI (MIWI) is degraded through the APC/C-26S proteasome pathway and that piRNAs play an indispensable role in this process by enhancing MIWI interaction with an APC/C substrate-binding subunit. Interestingly, piRNA-triggered MIWI destruction occurs in late spermatids, which in turn leads to piRNA elimination, suggesting a feedforward mechanism for coordinated removal of the MIWI/piRNA machinery at a specific developmental stage. Importantly, the proper removal of MIWI/piRNA is essential for sperm maturation. Together, our results reveal a role for piRNAs in regulating the clearance of the MIWI/piRNA machinery via the ubiquitin-proteosome pathway and demonstrate the critical importance of proper temporal regulation of MIWI/piRNA in male germ cell development.