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

FEBS Letters

article

Makoto Fukushima¹  Nao Hosoda¹  Kotaro Chifu¹  Shin-ichi Hoshino¹ 

[1] Department of Biological Chemistry, Graduate School of Pharmaceutical Sciences, Nagoya City University

关键词: ALS;    Caf1;    deadenylation;    mRNA decay;    TDP-43;    translation;   

DOI  :  10.1002/1873-3468.13310

来源: John Wiley & Sons Ltd.

【 摘 要 】

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 30 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 30 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.

【 授权许可】

Unknown