TDP‐43 accelerates deadenylation of target mRNAs by recruiting Caf1 deadenylase

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 instabili...

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Bibliographic Details
Published in:FEBS letters 2019-02, Vol.593 (3), p.277-287
Main Authors: Fukushima, Makoto, Hosoda, Nao, Chifu, Kotaro, Hoshino, Shin‐ichi
Format: Article
Language:English
Subjects:
3' Untranslated Regions
ALS
Amyotrophic Lateral Sclerosis - genetics
Amyotrophic Lateral Sclerosis - metabolism
Amyotrophic Lateral Sclerosis - pathology
Caf1
deadenylation
DNA-Binding Proteins - genetics
DNA-Binding Proteins - metabolism
Exoribonucleases - genetics
Exoribonucleases - metabolism
HEK293 Cells
HeLa Cells
Humans
mRNA decay
Progranulins - biosynthesis
Progranulins - genetics
RNA Stability
TDP‐43
translation
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Summary: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.
ISSN:0014-5793
1873-3468
DOI:10.1002/1873-3468.13310