PIWI-clade proteins harness pi RNAs of 24–33 nt in length.Of great puzzles are how PIWI-clade proteins incorporate pi RNAs of different sizes and whether the size matters to PIWI/pi RNA function.Here we report that a...PIWI-clade proteins harness pi RNAs of 24–33 nt in length.Of great puzzles are how PIWI-clade proteins incorporate pi RNAs of different sizes and whether the size matters to PIWI/pi RNA function.Here we report that a PIWI-Ins module unique in PIWIclade proteins helps define the length of pi RNAs.Deletion of PIWI-Ins in Miwi shifts MIWI to load with shorter pi RNAs and causes spermiogenic failure in mice,demonstrating the functional importance of this regulatory module.Mechanistically,we show that longer pi RNAs provide additional complementarity to target m RNAs,thereby enhancing the assembly of the MIWI/e IF3f/Hu R super-complex for translational activation.Importantly,we identify a c.1108C>T(p.R370W)mutation of HIWI(human PIWIL1)in infertile men and demonstrate in Miwi knock-in mice that this genetic mutation impairs male fertility by altering the property of PIWI-Ins in selecting longer pi RNAs.These findings reveal a critical role of PIWI-Ins-ensured longer pi RNAs in fine-tuning MIWI/pi RNA targeting capacity,proven essential for spermatid development and male fertility.展开更多
小分子调控RNA,包括siRNA(small interfering RNA)、miRNA(microRNA)和piRNA(piwi interacting RNA)、hsRNA(heterochromatin associated small RNA)等,是当前生命科学研究的前沿热点。越来越多的证据表明,这些小分子R N A存在于几乎所...小分子调控RNA,包括siRNA(small interfering RNA)、miRNA(microRNA)和piRNA(piwi interacting RNA)、hsRNA(heterochromatin associated small RNA)等,是当前生命科学研究的前沿热点。越来越多的证据表明,这些小分子R N A存在于几乎所有较高等的真核生物细胞中,对生物体具有非常重要的调控功能。它们通过各种序列特异性的RNA基因沉默作用,包括RNA干扰(RNAi)、翻译抑制、异染色质形成等,调控诸如生长发育、应激反应、沉默转座子等各种各样的细胞进程。随着对这些小分子调控RNA的发现,一些RNase III酶家族成员、Argonaute蛋白质家族成员及RNA结合蛋白质等先后被鉴定为小RNA的胞内蛋白质合作者,参与小RNA的加工成熟和在细胞内行使功能。本综述简介一些RNA沉默作用途径中重要组分的结构和功能的研究进展。展开更多
大量遗传学研究表明,Piwi蛋白对于动物生殖系细胞发育具有至关重要的作用,Piwi基因敲除致动物不育。人Piwi(Hiwi)基因特异性地在雄性生殖细胞表达,但目前对其在人精子发生中的作用及其与男性不育的联系还知之甚少。该研究通过筛查临床...大量遗传学研究表明,Piwi蛋白对于动物生殖系细胞发育具有至关重要的作用,Piwi基因敲除致动物不育。人Piwi(Hiwi)基因特异性地在雄性生殖细胞表达,但目前对其在人精子发生中的作用及其与男性不育的联系还知之甚少。该研究通过筛查临床男性不育样本发现,少弱精症患者Hiwi基因中存在拮抗泛素化修饰的D-box元件突变;通过构建基因敲入小鼠模型证实,该突变导致雄性不育。机制研究表明,小鼠Piwi(Miwi)D-box突变致MIWI蛋白异常稳定存在于后期精子细胞中,导致与其相互作用的组蛋白泛素连接酶RNF8(ring finger protein 8)被扣留于细胞质、不能入核催化组蛋白泛素化修饰,进而抑制组蛋白被鱼精蛋白替换,引发精子形成异常、雄性不育。该研究发现了男性不育的一类新型致病基因突变,并发现了Piwi蛋白具有调控组蛋白泛素化修饰的新功能,揭示了精子形成中调控组蛋白–鱼精蛋白转换的重要机制。展开更多
基金supported by the National Key Research and Development Program of China(2022YFA1303300,2021YFC2700200,2017YFA0504400)Chinese Academy of Sciences(“Strategic Priority Research Program”grants XDB37000000)+3 种基金the National Natural Science Foundation of China(31830109,31821004,91940305,31961133022,32101037,32271347,21933010,22203089)Science and Technology Commission of Shanghai Municipality(17JC1420100,2017SHZDZX01,19JC1410200,21YF1452700,21ZR1470500)the Young Elite Scientist Sponsorship Program of the China Association for Science and Technology(2021QNRC001)the Foundation of Key Laboratory of Gene Engineering of the Ministry of Education。
文摘PIWI-clade proteins harness pi RNAs of 24–33 nt in length.Of great puzzles are how PIWI-clade proteins incorporate pi RNAs of different sizes and whether the size matters to PIWI/pi RNA function.Here we report that a PIWI-Ins module unique in PIWIclade proteins helps define the length of pi RNAs.Deletion of PIWI-Ins in Miwi shifts MIWI to load with shorter pi RNAs and causes spermiogenic failure in mice,demonstrating the functional importance of this regulatory module.Mechanistically,we show that longer pi RNAs provide additional complementarity to target m RNAs,thereby enhancing the assembly of the MIWI/e IF3f/Hu R super-complex for translational activation.Importantly,we identify a c.1108C>T(p.R370W)mutation of HIWI(human PIWIL1)in infertile men and demonstrate in Miwi knock-in mice that this genetic mutation impairs male fertility by altering the property of PIWI-Ins in selecting longer pi RNAs.These findings reveal a critical role of PIWI-Ins-ensured longer pi RNAs in fine-tuning MIWI/pi RNA targeting capacity,proven essential for spermatid development and male fertility.
文摘大量遗传学研究表明,Piwi蛋白对于动物生殖系细胞发育具有至关重要的作用,Piwi基因敲除致动物不育。人Piwi(Hiwi)基因特异性地在雄性生殖细胞表达,但目前对其在人精子发生中的作用及其与男性不育的联系还知之甚少。该研究通过筛查临床男性不育样本发现,少弱精症患者Hiwi基因中存在拮抗泛素化修饰的D-box元件突变;通过构建基因敲入小鼠模型证实,该突变导致雄性不育。机制研究表明,小鼠Piwi(Miwi)D-box突变致MIWI蛋白异常稳定存在于后期精子细胞中,导致与其相互作用的组蛋白泛素连接酶RNF8(ring finger protein 8)被扣留于细胞质、不能入核催化组蛋白泛素化修饰,进而抑制组蛋白被鱼精蛋白替换,引发精子形成异常、雄性不育。该研究发现了男性不育的一类新型致病基因突变,并发现了Piwi蛋白具有调控组蛋白泛素化修饰的新功能,揭示了精子形成中调控组蛋白–鱼精蛋白转换的重要机制。
