NRDE2 acts as a negative regulator of the exosome complex by disrupting hMTR4 interactome

The RNA exosome complex is the most versatile RNA-degradation machine in eukaryotes that requires MTR4 for every aspect of its nuclear functions. To date, how exosome functions are negatively regulated remains largely unknown. Here, we report the identification of NRDE2 as an inhibitory regulator of exosome functions. NRDE2 tightly and directly interacts with human MTR4 (hMTR4) via its N-terminal domain, resulting in their mutual stabilization. Overexpression of NRDE2 attenuates associations of hMTR4 with the exosome, CBC, TRAMP and NEXT components, resulting in accumulation of exosome target RNAs as well as 3' extended 5.8S rRNAs. Conversely, in NRDE2 knockdown cells, the association of hMTR4 with CBC, TRAMP or NEXT components are significantly enhanced, accompanied by promoted RNA degradation. Together, our work uncovers NRDE2 as a direct negative regulator of exosome functions that prevents hMTR4 from associating with its interacting partners. Overall design: RNA levels were compared when NRDE2 is over expressed or knocked down by deep sequencing.

RNA外切酶体复合物（RNA exosome complex）是真核生物中功能最为多样的RNA降解机器，其核内功能的所有环节均依赖MTR4。截至目前，学界对RNA外切酶体功能的负调控机制仍知之甚少。本研究鉴定出NRDE2为RNA外切酶体功能的负调控因子。NRDE2通过其N端结构域与人类MTR4（hMTR4）紧密且直接结合，进而实现二者的相互稳定。过表达NRDE2会削弱hMTR4与RNA外切酶体、CBC、TRAMP及NEXT复合物组分的结合，导致RNA外切酶体靶标RNA以及3'端延伸的5.8S核糖体RNA（rRNAs）积累。反之，在NRDE2敲低的细胞中，hMTR4与CBC、TRAMP或NEXT复合物组分的结合显著增强，同时RNA降解过程也得到促进。综上，本研究揭示NRDE2是RNA外切酶体功能的直接负调控因子，可通过阻断hMTR4与其互作伴侣的结合发挥调控作用。实验整体设计：通过深度测序比较NRDE2过表达或敲低条件下的细胞RNA表达水平。