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  • Ribosomopathy-associated mutations cause proteotoxic stress that is alleviated by TOR inhibition.

Ribosomopathy-associated mutations cause proteotoxic stress that is alleviated by TOR inhibition.

Nature cell biology (2021-01-27)
Carles Recasens-Alvarez, Cyrille Alexandre, Joanna Kirkpatrick, Hisashi Nojima, David J Huels, Ambrosius P Snijders, Jean-Paul Vincent
ABSTRACT

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.

MATERIALS
Product Number
Brand
Product Description

Sigma-Aldrich
Anti-Ubiquitinylated proteins Antibody, clone FK2, clone FK2, Upstate®, from mouse
Sigma-Aldrich
DAPI, for nucleic acid staining
Supelco
Rapamycin, VETRANAL®, analytical standard
Sigma-Aldrich
G 418 disulfate salt solution, 50 mg/mL in H2O, 0.1 μm filtered, BioReagent, suitable for cell culture