Ribosomopathy-associated mutations cause proteotoxic stress that is alleviated by TOR inhibition
| Autor: | Carles Recasens-Alvarez, Cyrille Alexandre, Jean-Paul Vincent, Hisashi Nojima, Joanna Kirkpatrick, David J. Huels, Ambrosius P. Snijders |
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| Přispěvatelé: | Center of Experimental and Molecular Medicine, CCA - Cancer biology and immunology |
| Rok vydání: | 2019 |
| Předmět: |
Proteomics
Ribosomal Proteins Heterozygote autophagy Ribosomopathy Cell Apoptosis Protein degradation Biology Ribosome Article ribosomes 03 medical and health sciences Protein Aggregates proteotoxic stress 0302 clinical medicine Ribosomal protein medicine Protein biosynthesis Animals Humans Wings Animal Diamond Blackfan anemia Gene Alleles protein translation ribosomopathies 030304 developmental biology 0303 health sciences TOR Serine-Threonine Kinases Autophagy p62 RPS26 Proteins Cell Biology TOR Cell biology medicine.anatomical_structure Drosophila melanogaster HEK293 Cells Imaginal Discs 030220 oncology & carcinogenesis Protein Biosynthesis Mutation eIF2 RPS23 Signal Transduction |
| Zdroj: | Nature cell biology Nature cell biology, 23(2), 127-135. Nature Publishing Group |
| ISSN: | 1476-4679 1465-7392 |
| Popis: | Ribosomes are multicomponent molecular machines that synthesize all of the proteins of living cells. Most of the genes that encode the protein components of ribosomes are therefore essential. A reduction in gene dosage is often viable albeit deleterious and is associated with human syndromes, which are collectively known as ribosomopathies1–3. The cell biological basis of these pathologies has remained unclear. Here, we model human ribosomopathies in Drosophila and find widespread apoptosis and cellular stress in the resulting animals. This is not caused by insufficient protein synthesis, as reasonably expected. Instead, ribosomal protein deficiency elicits proteotoxic stress, which we suggest is caused by the accumulation of misfolded proteins that overwhelm the protein degradation machinery. We find that dampening the integrated stress response4 or autophagy increases the harm inflicted by ribosomal protein deficiency, suggesting that these activities could be cytoprotective. Inhibition of TOR activity—which decreases ribosomal protein production, slows down protein synthesis and stimulates autophagy5—reduces proteotoxic stress in our ribosomopathy model. Interventions that stimulate autophagy, combined with means of boosting protein quality control, could form the basis of a therapeutic strategy for this class of diseases. Recasens-Alvarez et al. model human ribosomopathies and find that apoptosis and cellular stress result from proteotoxic stress that overwhelms the degradation machinery. |
| Databáze: | OpenAIRE |
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