TDP-43 regulates its mRNA levels through a negative feedback loop
| Autor: | Ayala, Y. M., Conti, L. D., Avendaño Vázquez, S. E., Dhir, A., Romano, Maurizio, D'Ambrogio, A., Tollervey, J., Ule, J., Baralle, M., Buratti, Emanuele, Baralle, F. E. |
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| Přispěvatelé: | Y. M., Ayala, L. D., Conti, S. E., Avendaño Vázquez, A., Dhir, Romano, Maurizio, A., D'Ambrogio, J., Tollervey, J., Ule, M., Baralle, Buratti, Emanuele, F. E., Baralle |
| Jazyk: | angličtina |
| Rok vydání: | 2011 |
| Předmět: |
RNA Processing
DNA-Binding Protein Physiological Immunoblotting Molecular Sequence Data Messenger Post-Transcriptional Plasmid Polymerase Chain Reaction Article Cell Line Feedback Humans Immunoprecipitation Northern RNA Messenger RNA Processing Post-Transcriptional Gene Library Feedback Physiological Base Sequence Blotting Sequence Analysis DNA DNA Blotting Northern DNA-Binding Proteins Gene Expression Regulation Sequence Analysi Plasmids RNA Interference RNA Sequence Analysis Human |
| Popis: | TAR DNA-binding protein (TDP-43) is an evolutionarily conserved heterogeneous nuclear ribonucleoprotein (hnRNP) involved in RNA processing, whose abnormal cellular distribution and post-translational modification are key markers of certain neurodegenerative diseases, such as amyotrophic lateral sclerosis and frontotemporal lobar degeneration. We generated human cell lines expressing tagged forms of wild-type and mutant TDP-43 and observed that TDP-43 controls its own expression through a negative feedback loop. The RNA-binding properties of TDP-43 are essential for the autoregulatory activity through binding to 3' UTR sequences in its own mRNA. Our analysis indicated that the C-terminal region of TDP-43, which mediates TDP-43-hnRNP interactions, is also required for self-regulation. TDP-43 binding to its 3' UTR does not significantly change the pre-mRNA splicing pattern but promotes RNA instability. Moreover, blocking exosome-mediated degradation partially recovers TDP-43 levels. Our findings demonstrate that cellular TDP-43 levels are under tight control and it is likely that disease-associated TDP-43 aggregates disrupt TDP-43 self-regulation, thus contributing to pathogenesis. |
| Databáze: | OpenAIRE |
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