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

• Published in: Nature cell biology Vol. 23; no. 2; pp. 127 - 135
• Main Authors: Recasens-Alvarez, Carles, Alexandre, Cyrille, Kirkpatrick, Joanna, Nojima, Hisashi, Huels, David J., Snijders, Ambrosius P., Vincent, Jean-Paul
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 01-02-2021; Nature Publishing Group
• Subjects: 13; 13/2; 14/35; 38; 38/1; 631/80/304; 631/80/83; 64; 64/24; 82; 82/58; 82/80; Alleles; Animals; Apoptosis; Apoptosis - drug effects; Autophagy; Autophagy - drug effects; Biodegradation; Biomedical and Life Sciences; Cancer Research; Care and treatment; Cell Biology; Chemical synthesis; Complications and side effects; Degradation; Developmental Biology; Drosophila melanogaster - drug effects; Drosophila melanogaster - metabolism; Gene dosage; Gene mutations; Genetic aspects; Genetic disorders; Health aspects; HEK293 Cells; Heterozygote; Humans; Imaginal Discs - drug effects; Imaginal Discs - metabolism; Letter; Life Sciences; Medical research; Medicine, Experimental; Molecular machines; Mutation; Mutation - genetics; Phagocytosis; Protein Aggregates - drug effects; Protein biosynthesis; Protein Biosynthesis - drug effects; Protein deficiency; Protein folding; Protein kinases; Protein synthesis; Proteins; Proteins - toxicity; Proteolysis; Proteomics; Quality control; Ribosomal proteins; Ribosomal Proteins - biosynthesis; Ribosomes; Ribosomes - genetics; Ribosomes - pathology; Signal Transduction - drug effects; Stem Cells; Stress (Physiology); TOR Serine-Threonine Kinases - antagonists & inhibitors; TOR Serine-Threonine Kinases - metabolism; Wings, Animal - drug effects; Wings, Animal - metabolism; United Kingdom
• ISSN: 1465-7392; 1476-4679
• DOI: 10.1038/s41556-020-00626-1

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 ribosomopathies
1
–
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 response
4
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 autophagy
5
—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.