RNA-assisted sequestration of RNA-binding proteins by cytoplasmic inclusions of the C-terminal 35-kDa fragment of TDP-43

生物 核糖核酸 RNA结合蛋白 细胞质 RNA剪接 信使核糖核酸 细胞生物学 前体mRNA 分子生物学 生物化学 基因
作者
Leilei Jiang,Wen-Liang Guan,Jianyang Wang,Shuxian Zhang,Hong‐Yu Hu
出处
期刊:Journal of Cell Science [The Company of Biologists]
卷期号:135 (6) 被引量:11
标识
DOI:10.1242/jcs.259380
摘要

ABSTRACT TDP-43 (also known as TARDBP) is a nuclear splicing factor functioning in pre-mRNA processing. Its C-terminal 35-kDa fragment (TDP-35) forms inclusions or aggregates in cytoplasm, and sequesters full-length TDP-43 into the inclusions through binding with RNA. We extended the research to investigate whether TDP-35 inclusions sequester other RNA-binding proteins (RBPs) and how RNA-binding specificity has a role in this sequestration process. We have characterized T-cell restricted intracellular antigen-1 (TIA1) and other RBPs that can be sequestered into the TDP-35 inclusions through specific RNA binding, and found that this sequestration leads to the dysfunction of TIA1 in maturation of target pre-mRNA. Moreover, we directly visualized the dynamic sequestration of TDP-43 by the cytoplasmic TDP-35 inclusions by live-cell imaging. Our results demonstrate that TDP-35 sequesters some specific RBPs and this sequestration is assisted by binding with RNA in a sequence-specific manner. This study provides further evidence in supporting the hijacking hypothesis for RNA-assisted sequestration and will be beneficial to further understanding of the TDP-43 proteinopathies.
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