Nuclear RNA binding regulates TDP-43 nuclear localization and passive nuclear export.
Nuclear RNA binding regulates TDP-43 nuclear localization and passive nuclear export.
复制标题
DOI：
10.1016/j.celrep.2022.111106
复制
发表时间：
2022-07-19
期刊：
影响因子：
8.8
通讯作者：
Hayes, Lindsey R.
中科院分区：
文献类型：
--
作者：
Duan, Lauren;Zaepfel, Benjamin L.;Aksenova, Vasilisa;Dasso, Mary;Rothstein, Jeffrey D.;Kalab, Petr;Hayes, Lindsey R.
rna结合蛋白TDP-43的核清除是神经变性的标志，也是重要的治疗靶点。我们目前对TDP-43核胞质转运的理解并不能完全解释其在疾病中主要的核定位或错定位。在这里，我们发现TDP-43通过被动扩散退出细胞核，独立于mRNA的促进输出。RNA聚合酶II阻断和RNase处理诱导TDP-43核外排，表明核RNA将TDP-43隔离在细胞核内，限制了其被动输出的可用性。短的富含谷氨酸的低聚物诱导TDP-43的核外排（可能是通过与内源性核rna结合的TDP-43竞争），以及剪接抑制带来的核保留，表明TDP-43的核定位依赖于与富含谷氨酸的核rna的结合。事实上，rna结合域突变显著降低了TDP-43的核定位，并消除了转录阻滞诱导的核外排。因此，gu -RNA的核丰度，由转录、pre-mRNA加工和RNA输出的平衡决定，调节TDP-43的核定位。Duan等人证明TDP-43的核输出是通过核孔通道被动扩散发生的，并受到核中富含gu的RNA结合的限制。调节核RNA丰度或TDP-43-RNA结合的过程（如转录、剪接和mRNA的输出）调节TDP-43的核定位和输出的可用性。
Nuclear clearance of the RNA-binding protein TDP-43 is a hallmark of neurodegeneration and an important therapeutic target. Our current understanding of TDP-43 nucleocytoplasmic transport does not fully explain its predominantly nuclear localization or mislocalization in disease. Here, we show that TDP-43 exits nuclei by passive diffusion, independent of facilitated mRNA export. RNA polymerase II blockade and RNase treatment induce TDP-43 nuclear efflux, suggesting that nuclear RNAs sequester TDP-43 in nuclei and limit its availability for passive export. Induction of TDP-43 nuclear efflux by short, GU-rich oligomers (presumably by outcompeting TDP-43 binding to endogenous nuclear RNAs), and nuclear retention conferred by splicing inhibition, demonstrate that nuclear TDP-43 localization depends on binding to GU-rich nuclear RNAs. Indeed, RNA-binding domain mutations markedly reduce TDP-43 nuclear localization and abolish transcription blockade-induced nuclear efflux. Thus, the nuclear abundance of GU-RNAs, dictated by the balance of transcription, pre-mRNA processing, and RNA export, regulates TDP-43 nuclear localization. Duan et al. demonstrate that TDP-43 nuclear export occurs by passive diffusion through nuclear pore channels and is restricted by nuclear GU-rich RNA binding. Processes that modulate nuclear RNA abundance or TDP-43-RNA binding—such as transcription, splicing, and mRNA export—regulate TDP-43 nuclear localization and availability for export.
登录
查看更多内容
影响因子：
16.6
作者：
Cha HJ;Uyan Ö;Kai Y;Liu T;Zhu Q;Tothova Z;Botten GA;Xu J;Yuan GC;Dekker J;Orkin SH
通讯作者：
Orkin SH
影响因子：
5.8
作者：
Bresson S;Tollervey D
通讯作者：
Tollervey D
影响因子：
16.6
作者：
Cohen, Todd J.;Hwang, Andrew W.;Restrepo, Clark R.;Yuan, Chao-Xing;Trojanowski, John Q.;Lee, Virginia M. Y.
通讯作者：
Lee, Virginia M. Y.
影响因子：
5.4
作者：
Bruun GH;Doktor TK;Borch-Jensen J;Masuda A;Krainer AR;Ohno K;Andresen BS
通讯作者：
Andresen BS
影响因子：
4
作者：
Ayala, Youhna M.;Zago, Paola;Baralle, Francisco E.
通讯作者：
Baralle, Francisco E.