Exosome cofactor hMTR 4 competes with export adaptor ALYREF to ensure balanced nuclear RNA pools for degradation and export

• Published in: The EMBO journal Vol. 36; no. 19; pp. 2870 - 2886
• Main Authors: Fan, Jing, Kuai, Bin, Wu, Guifen, Wu, Xudong, Chi, Binkai, Wang, Lantian, Wang, Ke, Shi, Zhubing, Zhang, Heng, Chen, She, He, Zhisong, Wang, Siyuan, Zhou, Zhaocai, Li, Guohui, Cheng, Hong
• Format: Journal Article
• Language: English
• Published: 02.10.2017
• ISSN: 0261-4189; 1460-2075
• DOI: 10.15252/embj.201696139

Abstract The exosome is a key RNA machine that functions in the degradation of unwanted RNA s. Here, we found that significant fractions of precursors and mature forms of mRNA s and long noncoding RNA s are degraded by the nuclear exosome in normal human cells. Exosome‐mediated degradation of these RNA s requires its cofactor hMTR 4. Significantly, hMTR 4 plays a key role in specifically recruiting the exosome to its targets. Furthermore, we provide several lines of evidence indicating that hMTR 4 executes this role by directly competing with the mRNA export adaptor ALYREF for associating with ARS 2, a component of the cap‐binding complex ( CBC ), and this competition is critical for determining whether an RNA is degraded or exported to the cytoplasm. Together, our results indicate that the competition between hMTR 4 and ALYREF determines exosome recruitment and functions in creating balanced nuclear RNA pools for degradation and export. Synopsis image Competition of the hMTR 4 helicase and the mRNA export adaptor ALYREF for interaction with the nuclear cap‐binding complex determines the specificity of exosome recruitment to nuclear RNA s, forming a checkpoint to ensure that only functional mRNA s and lnc RNA s are exported to the cytoplasm. Disruption of mRNA processing and export in human cells triggers significant mRNA and lncRNA degradation by the nuclear exosome. hMTR4 triggers RNA decay by directing the nuclear exosome to specific targets. hMTR4 and export receptor ALYREF compete for the binding to the nuclear cap‐binding complex. The competition between hMTR4 and ALYREF determines if nuclear RNA pools are destined for degradation or export.