State Key Laboratory of Molecular Biology, Shanghai Key Laboratory of Molecular Andrology, Institute of Biochemistry and Cell Biology, Center for Excellence in Molecular Cell Science, Chinese Academy of Sciences, Shanghai, China.
School of Life Science, Hangzhou Institute for Advanced Study, University of Chinese Academy of Sciences, Hangzhou China.
Biol Reprod. 2022 Jul 25;107(1):101-108. doi: 10.1093/biolre/ioac073.
PIWI proteins and PIWI-interacting RNAs (piRNAs) are specifically expressed in animal germlines and play essential roles during gametogenesis in animals. The primary function of PIWI/piRNAs is known to silence transposable elements for protecting genome integrity in animal germlines, while their roles beyond silencing transposons are also documented by us and others. In particular, we show that mouse PIWIL1 (MIWI)/piRNAs play a dual role in regulating protein-coding genes in mouse spermatids through interacting with different protein factors in a developmental stage-dependent manner, including translationally activating a subset of AU-rich element-containing mRNAs in round spermatids and inducing massive mRNA degradation in late spermatids. We further show that MIWI is eliminated through the ubiquitin-26S proteasome pathway during late spermiogenesis. By exploring the biological function of MIWI ubiquitination by APC/C, we identified ubiquitination-deficient mutations in human PIWIL1 of infertile men and further established their causative role in male infertility in mouse model, supporting PIWIL1 as a human male infertility-relevant gene. Additionally, we reported that PIWIL1, aberrantly induced in human tumors, functions as an oncoprotein in a piRNA-independent manner in cancer cells. In the current review, we summarize our latest findings regarding the roles and mechanisms of PIWIL1 and piRNAs in mouse spermatids and human diseases, and discuss the related works in the field.
PIWI 蛋白和 PIWI 相互作用的 RNA（piRNAs）特异性地在动物生殖细胞中表达，在动物配子发生过程中发挥重要作用。PIWI/piRNAs 的主要功能是沉默转座元件，以保护动物生殖细胞中的基因组完整性，而我们和其他人也记录了它们超越沉默转座子的作用。特别是，我们表明，小鼠 PIWIL1（MIWI）/piRNAs 通过与不同的蛋白因子在发育阶段依赖性地相互作用，在调节小鼠精原细胞中的蛋白质编码基因方面发挥双重作用，包括在圆形精原细胞中翻译激活一组含有 AU 丰富元件的 mRNAs，并在晚期精原细胞中诱导大量 mRNA 降解。我们进一步表明，MIWI 在晚期精子发生过程中通过泛素-26S 蛋白酶体途径被消除。通过探索 APC/C 对 MIWI 泛素化的生物学功能，我们鉴定出了不育男性中人类 PIWIL1 的泛素化缺陷突变，并在小鼠模型中进一步确立了它们在男性不育中的因果作用，支持 PIWIL1 作为一个与人类男性不育相关的基因。此外，我们还报道了在人类肿瘤中异常诱导的 PIWIL1 在癌细胞中以一种与 piRNA 无关的方式作为癌蛋白发挥作用。在当前的综述中，我们总结了我们在小鼠精原细胞和人类疾病中关于 PIWIL1 和 piRNAs 的作用和机制的最新发现，并讨论了该领域的相关工作。
