Direct evidence that Ataxin-2 is a translational activator mediating cytoplasmic polyadenylation
| Autor: | Hitomi Tsuiji, Shin-ichi Hoshino, Hiroto Inagaki, Nao Hosoda |
|---|---|
| Rok vydání: | 2020 |
| Předmět: |
0301 basic medicine
Cytoplasm Polyadenylation RNA Stability RNA-binding protein Biochemistry Poly(A)-Binding Protein I 03 medical and health sciences PABPC1 Polysome Translational regulation medicine Humans Editors' Picks RNA Messenger Molecular Biology Ataxin-2 mRNA Cleavage and Polyadenylation Factors Messenger RNA 030102 biochemistry & molecular biology Chemistry Neurodegeneration Polynucleotide Adenylyltransferase Cell Biology medicine.disease Cell biology 030104 developmental biology HEK293 Cells Ataxin Protein Biosynthesis HeLa Cells Protein Binding |
| Zdroj: | J Biol Chem |
| ISSN: | 1083-351X |
| Popis: | 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 (i.e. TDP-43 proteinopathies), and this process could be a therapeutic target for Ataxin-2–related neurodegenerative disorders. |
| Databáze: | OpenAIRE |
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