Direct evidence that Ataxin-2 is a translational activator mediating cytoplasmic polyadenylation.
Ataxin-2
/ genetics
Cytoplasm
/ genetics
HEK293 Cells
HeLa Cells
Humans
Poly(A)-Binding Protein I
/ genetics
Polyadenylation
Polynucleotide Adenylyltransferase
/ genetics
Protein Binding
Protein Biosynthesis
RNA Stability
RNA, Messenger
/ genetics
mRNA Cleavage and Polyadenylation Factors
/ genetics
Ataxin-2
PAPD4
RNA metabolism
RNA processing
RNA turnover
RNA-binding protein
TDP-43
cytoplasmic polyadenylation
polyadenylation
polyglutamine disease
translation control
translation regulation
Journal
The Journal of biological chemistry
ISSN: 1083-351X
Titre abrégé: J Biol Chem
Pays: United States
ID NLM: 2985121R
Informations de publication
Date de publication:
20 11 2020
20 11 2020
Historique:
received:
12
04
2020
revised:
13
09
2020
pubmed:
30
9
2020
medline:
10
3
2021
entrez:
29
9
2020
Statut:
ppublish
Résumé
The RNA-binding protein Ataxin-2 binds to and stabilizes a number of mRNA sequences, including that of the transactive response DNA-binding protein of 43 kDa (TDP-43). Ataxin-2 is additionally involved in several processes requiring translation, such as germline formation, long-term habituation, and circadian rhythm formation. However, it has yet to be unambiguously demonstrated that Ataxin-2 is actually involved in activating the translation of its target mRNAs. Here we provide direct evidence from a polysome profile analysis showing that Ataxin-2 enhances translation of target mRNAs. Our recently established method for transcriptional pulse-chase analysis under conditions of suppressing deadenylation revealed that Ataxin-2 promotes post-transcriptional polyadenylation of the target mRNAs. Furthermore, Ataxin-2 binds to a poly(A)-binding protein PABPC1 and a noncanonical poly(A) polymerase PAPD4 via its intrinsically disordered region (amino acids 906-1095) to recruit PAPD4 to the targets. Post-transcriptional polyadenylation by Ataxin-2 explains not only how it activates translation but also how it stabilizes target mRNAs, including TDP-43 mRNA. Ataxin-2 is known to be a potent modifier of TDP-43 proteinopathies and to play a causative role in the neurodegenerative disease spinocerebellar ataxia type 2, so these findings suggest that Ataxin-2-induced cytoplasmic polyadenylation and activation of translation might impact neurodegeneration (
Identifiants
pubmed: 32989052
pii: S0021-9258(17)50411-1
doi: 10.1074/jbc.RA120.013835
pmc: PMC7681009
pii:
doi:
Substances chimiques
ATXN2 protein, human
0
Ataxin-2
0
Poly(A)-Binding Protein I
0
RNA, Messenger
0
mRNA Cleavage and Polyadenylation Factors
0
Polynucleotide Adenylyltransferase
EC 2.7.7.19
TENT2 protein, human
EC 2.7.7.19
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
15810-15825Informations de copyright
© 2020 Inagaki et al.
Déclaration de conflit d'intérêts
Conflict of interest—The authors declare that they have no conflicts of interest with the contents of this article.
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