Increased cytoplasmic TDP-43 reduces global protein synthesis by interacting with RACK1 on polyribosomes
| Autor: | Benjamin Wolozin, Federico La Regina, Antonino Cattaneo, Raffaella Scardigli, Melissa E. Murray, Marcello Ceci, Dennis W. Dickson, Arianna Russo, Nicla Romano |
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| Přispěvatelé: | Russo, Arianna, Scardigli, Raffaella, La Regina, Federico, Murray, Melissa E, Romano, Nicla, Dickson, Dennis W, Wolozin, Benjamin, Cattaneo, Antonino, Ceci, Marcello |
| Rok vydání: | 2017 |
| Předmět: |
0301 basic medicine
Cytoplasm Cytoplasmic inclusion RNA-binding protein Ribosome Neuroblastoma 0302 clinical medicine Protein biosynthesis Cell Nucleu Genetics (clinical) Motor Neurons General Medicine Neoplasm Proteins Cell biology DNA-Binding Proteins Frontotemporal Dementia Polyribosome Corrigendum GTP-Binding Protein Human DNA-Binding Protein RNA Splicing Receptors Cell Surface Biology Motor Neuron Receptors for Activated C Kinase Neoplasm Protein 03 medical and health sciences GTP-Binding Proteins Ribosomal protein Polysome mental disorders Genetics Humans RNA Messenger Molecular Biology Cell Nucleus Protein Biosynthesi Amyotrophic Lateral Sclerosis nutritional and metabolic diseases RNA nervous system diseases 030104 developmental biology Gene Expression Regulation Polyribosomes Protein Biosynthesis Mutation Ribosomes 030217 neurology & neurosurgery Amyotrophic Lateral Sclerosi |
| Zdroj: | Human Molecular Genetics. 26:1407-1418 |
| ISSN: | 1460-2083 0964-6906 |
| DOI: | 10.1093/hmg/ddx035 |
| Popis: | TDP-43 is a well known RNA binding protein involved in the pathogenesis of Amyotrophic Lateral Sclerosis (ALS) and Frontotemporal Lobar Dementia (FTLD). In physiological conditions, TDP-43 mainly localizes in the nucleus and shuttles, at least in neurons, to the cytoplasm to form TDP-43 RNA granules. In the nucleus, TDP-43 participates to the expression and splicing of RNAs, while in the cytoplasm its functions range from transport to translation of specific mRNAs. However, if loss or gain of these TDP-43 functions are affected in ALS/FTLD pathogenesis is not clear. Here, we report that TDP-43 localizes on ribosomes not only in primary neurons but also in SH-SY5Y human neuroblastoma cells. We find that binding of TDP-43 to the translational machinery is mediated by an interaction with a specific ribosomal protein, RACK1, and that an increase in cytoplasmic TDP-43 represses global protein synthesis, an effect which is rescued by overexpression of RACK1. Ribosomal loss of RACK1, which excludes TDP-43 from the translational machinery, remarkably reduces formation of TDP-43 cytoplasmic inclusions in neuroblastoma cells. Finally, we corroborate the interaction between TDP-43 and RACK1 on polyribosomes of neuroblastoma cells with mis-localization of RACK1 on TDP-43 positive cytoplasmic inclusions in motor neurons of ALS patients. In conclusions, results from this study suggest that TDP-43 represents a translational repressor not only for specific mRNAs but for overall translation and that its binding to polyribosomes through RACK1 may promote, under conditions inducing ALS pathogenesis, the formation of cytoplasmic inclusions. |
| Databáze: | OpenAIRE |
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