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. RNA levels were compared when NRDE2 is over expressed or knocked down by deep sequencing.