Argonaute proteins use nucleic acid guides to find and bind specific DNA or RNA target sequences. Argonaute proteins can be found in all kingdoms of life, and play diverse biological functions including genome defense, gene regulation, and chromosome partitioning. Many Argonautes retain their ancestral endoribonuclease activity, cleaving the phosphodiester bond between target nucleotides t10 and t11. In animals, a specialized class of Argonautes, the PIWI proteins, use 21–35 nt PIWI-interacting RNAs (piRNAs) to direct transposon silencing, protect the germline genome, and regulate gene expression during gametogenesis¹. The piRNA pathway is required for fertility in one or both sexes of nearly all animals. Both piRNA production and function require RNA cleavage catalyzed by PIWI proteins. Spermatogenesis in mice and other placental mammals requires three distinct, developmentally regulated PIWI proteins: MIWI (PIWIL1), MILI (PIWIL2), and MIWI2 (PIWIL4)^2–4. The piRNA-guided endoribonuclease activities of MIWI and MILI are essential to produce functional sperm^5,6. piRNA-directed silencing in mice and insects also requires Gametocyte-Specific Factor 1 (GTSF1), a PIWI-associated protein of unknown function^7–12. Here, we report that GTSF1 potentiates the weak, intrinsic, piRNA-directed RNA cleavage activities of PIWI proteins, transforming them into efficient endoribonucleases. GTSF1 represents the first example of an auxiliary protein that potentiates the catalytic activity of an Argonaute protein.

Argonaute 蛋白使用核酸向导来寻找和结合特定的 DNA 或 RNA 目标序列。Argonaute 蛋白存在于生命的各个领域，发挥着多种生物学功能，包括基因组防御、基因调控和染色体分区。许多 Argonautes 保留了其祖先的内切核糖核酸酶活性，可切割目标核苷酸 t10 和 t11 之间的磷酸二酯键。在动物中，一类专门的 Argonautes，即 PIWI 蛋白，使用 21-35 nt PIWI 相互作用的 RNA (piRNA) 来指导转座子沉默，保护种系基因组，并在配子发生过程中调节基因表达¹. 几乎所有动物的一种或两种性别的生育能力都需要 piRNA 通路。piRNA 的产生和功能都需要 PIWI 蛋白催化的 RNA 裂解。小鼠和其他胎盘哺乳动物的精子发生需要三种不同的、发育调节的 PIWI 蛋白：MIWI (PIWIL1)、MILI (PIWIL2) 和 MIWI2 (PIWIL4) ^2–4。MIWI 和 MILI 的 piRNA 引导的核糖核酸内切酶活性对于产生功能性精子^5,6至关重要。piRNA 在小鼠和昆虫中的定向沉默也需要配子体特异性因子 1 (GTSF1)，一种功能未知的 PIWI 相关蛋白^7–12. 在这里，我们报告 GTSF1 增强了 PIWI 蛋白弱的、内在的、piRNA 定向的 RNA 切割活性，将它们转化为有效的内切核糖核酸酶。GTSF1 代表了增强 Argonaute 蛋白催化活性的辅助蛋白的第一个例子。