Institute of Molecular Biotechnology of the Austrian Academy of Sciences (IMBA), Vienna BioCenter, Vienna, Austria.
Structural Biology Program, Memorial Sloan Kettering Cancer Center, New York, NY, USA.
Nat Struct Mol Biol. 2019 Aug;26(8):720-731. doi: 10.1038/s41594-019-0270-6. Epub 2019 Aug 5.
The PIWI-interacting RNA (piRNA) pathway protects genome integrity in part through establishing repressive heterochromatin at transposon loci. Silencing requires piRNA-guided targeting of nuclear PIWI proteins to nascent transposon transcripts, yet the subsequent molecular events are not understood. Here, we identify SFiNX (silencing factor interacting nuclear export variant), an interdependent protein complex required for Piwi-mediated cotranscriptional silencing in Drosophila. SFiNX consists of Nxf2-Nxt1, a gonad-specific variant of the heterodimeric messenger RNA export receptor Nxf1-Nxt1 and the Piwi-associated protein Panoramix. SFiNX mutant flies are sterile and exhibit transposon derepression because piRNA-loaded Piwi is unable to establish heterochromatin. Within SFiNX, Panoramix recruits heterochromatin effectors, while the RNA binding protein Nxf2 licenses cotranscriptional silencing. Our data reveal how Nxf2 might have evolved from an RNA transport receptor into a cotranscriptional silencing factor. Thus, NXF variants, which are abundant in metazoans, can have diverse molecular functions and might have been coopted for host genome defense more broadly.
PIWI 相互作用 RNA（piRNA）途径通过在转座子基因座建立抑制性异染色质来部分保护基因组完整性。沉默需要 piRNA 指导核 PIWI 蛋白靶向新生转座子转录物，但随后的分子事件尚不清楚。在这里，我们鉴定了 SFiNX（沉默因子相互作用核输出变体），这是一种在果蝇中需要 Piwi 介导的共转录沉默的相互依赖的蛋白质复合物。SFiNX 由 Nxf2-Nxt1 组成，这是一种二聚体 mRNA 输出受体 Nxf1-Nxt1 的性腺特异性变体，以及与 Piwi 相关的蛋白 Panoramix。SFiNX 突变体果蝇不育，并表现出转座子去抑制，因为加载 piRNA 的 Piwi 无法建立异染色质。在 SFiNX 内，Panoramix 招募异染色质效应因子，而 RNA 结合蛋白 Nxf2 则许可共转录沉默。我们的数据揭示了 Nxf2 如何从 RNA 运输受体进化为共转录沉默因子。因此，在后生动物中大量存在的 NXF 变体可以具有不同的分子功能，并且可能更广泛地被用于宿主基因组防御。
