Journal
JOURNAL OF CELL SCIENCE
Volume 135, Issue 6, Pages -Publisher
COMPANY BIOLOGISTS LTD
DOI: 10.1242/jcs.259380
Keywords
TDP-43; RNA-assisted sequestration; RNA-binding protein; TIA1; Cytoplasmic inclusion; Live-cell imaging
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Funding
- National Natural Science Foundation of China [31670782, 31700669, 31870764]
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This study found that the C-terminal fragment TDP-35 of the TDP-43 protein forms inclusions in the cytoplasm and sequesters other RNA-binding proteins (RBPs) through specific RNA binding, leading to dysfunction in target mRNA maturation. The sequestration process is assisted by sequence-specific RNA binding.
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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