NRDE2调控RNA外切体介导的RNA加工和降解的功能与分子机制研究

The whole life cycle of RNAs is tightly controlled by the RNA surveillance machine, for which the exosome complex is an important part. To achieve its full in vivo functions, the exosome associates with many co-factors, among which MTR4 is required for every aspect of nuclear exosome functions. Up to date, proteins that have been identified to associate with MTR4 all facilitate exosome function. How the roles of exosome are negatively regulated remains unclear. Here, we identified NRDE2 as an associating factor of hMTR4. Interestingly, our preliminary results show that overexpression of NRDE2 inhibits RNA degradation. In this proposal, we plan to combine biochemical and molecular biological methods to systematically study the interaction between NRDE2 and hMTR4, investigate the role of NRDE2 in exosome-dependent RNA degradation and processing， and explore the underlying mechanism. Together, our work potentially uncovers NRDE2 as the first negative regulator of the exosome. This work will significantly advance our understanding for regulation of exosome functions.

RNA exosome复合体（RNA外切体）是真核细胞RNA质量监控系统的重要组成部分。RNA解旋酶MTR4是exosome的所有细胞核功能不可或缺的co-factor。以往的研究发现MTR4通过与多种蛋白或蛋白复合物结合正向调控exosome的功能。迄今为止，细胞内是否存在exosome的负调控因子还不清楚。我们的前期结果发现在高等真核生物中功能完全未知的蛋白NRDE2与人源MTR4（hMTR4）结合，并抑制exosome的底物RNA的降解。本项目中，我们将综合利用生物化学，分子生物学和转录组学等手段，系统研究NRDE2与hMTR4之间的相互作用；调查NRDE2在调控exosome介导的RNA加工和降解中的功能；探究其功能发挥的分子机制。此研究可能发现首个exosome的负调控因子，对于我们理解exosome功能的调控机制有重要意义。

RNA exosome复合体是真核RNA质量监控系统的重要组成部分。最新研究发现，它不仅在细胞核内清除异常的RNA，还通过降解正常RNA来调控出核转运至细胞质内的RNA的量。 MTR4是exosome的所有细胞核功能不可或缺的co-factor。以往研究发现MTR4通过与多种蛋白或蛋白复合物结合正向调控exosome，细胞内是否存在exosome的负调控因子至今还不清楚。我们的前期结果发现在高等真核生物中功能完全未知的蛋白NRDE2与人源MTR4（hMTR4）结合，并抑制exosome的底物RNA的降解。在本项目中，我们综合利用了生物化学，分子生物学和转录组学手段，系统研究NRDE2与hMTR4之间的相互作用；调查NRDE2在调控exosome介导的RNA降解中的功能；探究其功能发挥的分子机制。我们鉴定到首个RNA外切复合体（the RNA exosome complex）的负调控因子NRDE2，阐释了NRDE2抑制RNA外切复合体的多层次功能，提供了一种RNA出核和降解的重要调控模式。