期刊
FEBS LETTERS
卷 593, 期 3, 页码 277-287出版社
WILEY
DOI: 10.1002/1873-3468.13310
关键词
ALS; Caf1; deadenylation; mRNA decay; TDP-43; translation
资金
- Japan Society for the Promotion of Science [25291004]
- Program on the Innovative Development and the Application of New Drugs for Hepatitis B from Japan Agency for Medical Research and development, AMED [JP17fk03 10111h0]
- Nagoya City University
- Takeda Science Foundation
TAR DNA-binding protein 43 (TDP-43) is an RNA-binding protein, whose loss-of-function mutation causes amyotrophic lateral sclerosis (ALS) and frontotemporal lobar degeneration. Recent studies demonstrated that TDP-43 binds to the 3 ' untranslated region (UTR) of target mRNAs to promote mRNA instability. Here, we show that TDP-43 recruits Caf1 deadenylase to mRNA targets and accelerates their deadenylation. Tethering TDP-43 to the mRNA 3 ' UTR recapitulates destabilization of the mRNA, and TDP-43 accelerates their deadenylation. This accelerated deadenylation is inhibited by a dominant negative mutant of Caf1. We find that TDP-43 physically interacts with Caf1. In addition, we provide evidence that TDP-43 regulates poly(A) tail length of endogenous Progranulin (GRN) mRNA. These results may shed light on the link between dysregulation of TDP-43-mediated mRNA deadenylation and pathogenesis of neurodegenerative diseases.
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