Che Mei-Xia, Jiang Lei-Lei, Li Hai-Yin, Jiang Ya-Jun, Hu Hong-Yu
State Key Laboratory of Molecular Biology, Institute of Biochemistry and Cell Biology, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai 200031, China.
State Key Laboratory of Molecular Biology, Institute of Biochemistry and Cell Biology, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai 200031, China.
FEBS Lett. 2015 Jul 8;589(15):1920-8. doi: 10.1016/j.febslet.2015.06.009. Epub 2015 Jun 19.
TDP-43 (TAR DNA binding protein of 43 kDa) and its C-terminal fragments are thought to be linked to the pathologies of amyotrophic lateral sclerosis and frontotemporal lobar degeneration. Here, we demonstrate that the aggregates or inclusions formed by its 35-kDa fragment (namely TDP-35) sequester full-length TDP-43 into cytoplasmic inclusions; and this sequestration is mediated by binding with RNA that is enriched in the cytoplasmic inclusions. RNA recognition motif 1 (RRM1) of TDP-43/TDP-35 plays a dominant role in nucleic-acid binding; mutation in this moiety abrogates formation of the TDP-35 inclusions and its RNA-assisted association with TDP-43. Thus, TDP-35 is able to sequester TDP-43 from nuclear localization into cytoplasmic inclusions, and RNA binding plays an essential role in this process.
TDP-43（43 kDa的TAR DNA结合蛋白）及其C末端片段被认为与肌萎缩侧索硬化症和额颞叶痴呆的病理过程有关。在此，我们证明由其35 kDa片段（即TDP-35）形成的聚集体或包涵体将全长TDP-43隔离到细胞质包涵体中；并且这种隔离是通过与富含在细胞质包涵体中的RNA结合来介导的。TDP-43/TDP-35的RNA识别基序1（RRM1）在核酸结合中起主导作用；该部分的突变消除了TDP-35包涵体的形成及其与TDP-43的RNA辅助结合。因此，TDP-35能够将TDP-43从核定位隔离到细胞质包涵体中，并且RNA结合在这一过程中起着至关重要的作用。
