HRDE-2 drives small RNA specificity for the nuclear Argonaute protein HRDE-1

• Published in: Nature communications 2024-02, Vol.15 (1), p.957-957, Article 957
• Main Authors: Chen, Shihui, Phillips, Carolyn M.
• Format: Article
• Language: English
• Subjects: 14; 14/1; 14/35; 14/63; 38; 38/91; 631/136/2434; 631/208/176/2016; 631/337/384/2053; 631/80/642; 64; 64/11; Biosynthesis; Gene expression; Gene silencing; Genomes; Granular materials; Humanities and Social Sciences; multidisciplinary; Proteins; Ribonucleic acid; RNA; RNA polymerase; RNA-mediated interference; Science; Science (multidisciplinary)
• ISSN: 2041-1723; 2041-1723
• DOI: 10.1038/s41467-024-45245-8

RNA interference (RNAi) is a conserved gene silencing process that exists in diverse organisms to protect genome integrity and regulate gene expression. In C. elegans , the majority of RNAi pathway proteins localize to perinuclear, phase-separated germ granules, which are comprised of sub-domains referred to as P granules, Mutator foci, Z granules, and SIMR foci. However, the protein components and function of the newly discovered SIMR foci are unknown. Here we demonstrate that HRDE-2 localizes to SIMR foci and interacts with the germline nuclear Argonaute HRDE-1 in its small RNA unbound state. In the absence of HRDE-2, HRDE-1 exclusively loads CSR-class 22G-RNAs rather than WAGO-class 22G-RNAs, resulting in inappropriate H3K9me3 deposition on CSR-target genes. Thus, our study demonstrates that the recruitment of unloaded HRDE-1 to germ granules, mediated by HRDE-2, is critical to ensure that the correct small RNAs are used to guide nuclear RNA silencing in the C. elegans germline. Argonaute proteins are loaded with small RNAs to confer target RNA specificity and proper gene silencing. Here, the authors establish that HRDE-2 recruits the unloaded nuclear Argonaute HRDE-1 to germ granules to facilitate correct small RNA loading.