GLH/VASA helicases promote germ granule formation to ensure the fidelity of piRNA-mediated transcriptome surveillance

The ability to distinguish non-self from self is the key characteristic for any defense system. piRNAs function as guardians of the genome by silencing non-self nucleic acids and transposable elements in animals. Many piRNA factors are enriched in perinuclear germ granules, but whether their localization is required for piRNA biogenesis or function is not known. Here we show that GLH/VASA helicase mutants exhibit defects in forming perinuclear condensates containing PIWI and other small RNA cofactors. These mutant animals produce largely normal levels of piRNA but are defective in triggering piRNA silencing. Strikingly, while many piRNA targets are activated in GLH mutants, we observed that hundreds of endogenous genes are aberrantly silenced by piRNAs. This defect in self versus non-self recognition was also observed in other mutants where perinuclear P granules are disrupted. Together, our results argue that perinuclear germ granules function critically to promote the fidelity of piRNA-based transcriptome surveillance in C. elegans and preserve self versus non-self distinction.

区分非己与自身的能力是任何防御系统的核心特征。Piwi相互作用RNA（piRNA）作为基因组的守护者，通过沉默动物体内的非己核酸与转座因子发挥功能。众多piRNA相关因子富集于核周生殖颗粒（perinuclear germ granules）中，但其定位是否对piRNA生物发生或功能不可或缺，目前尚无定论。本研究证实，GLH/VASA解旋酶突变体在组装包含PIWI蛋白（PIWI）与其他小RNA辅助因子的核周凝聚体时存在缺陷。此类突变体的piRNA整体表达水平基本正常，但无法正常触发piRNA沉默过程。值得注意的是，尽管诸多piRNA靶基因在GLH突变体中被激活，我们却观察到数百个内源基因被piRNA异常沉默。这种非己与自身的识别缺陷，同样出现在其他核周P颗粒（perinuclear P granules）被破坏的突变体中。综上，我们的研究结果表明，核周生殖颗粒在秀丽隐杆线虫（C. elegans）中发挥着关键作用，可促进基于piRNA的转录组监测的保真度，并维持非己与自身的识别区分。