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Ribosomal protein deficiency generates proteotoxic stress that is alleviated by TOR inhibition

ABSTRACT: Ribosomes are multi-component molecular machines that synthesize all the proteins of living cells. Understandably, most genes encoding the protein components of ribosomes are essential. Reduction in gene dosage is often viable but deleterious and associated with human syndromes, collectively known as ribosomopathies. 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 or autophagy worsens the harm inflicted by ribosomal protein deficiency, suggesting that these activities could be cytoprotective. Inhibition of TOR activity, which dampens ribosomal protein production, slows down protein synthesis and stimulates autophagy, 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.

INSTRUMENT(S): Orbitrap Fusion Lumos

ORGANISM(S): Drosophila Melanogaster (fruit Fly)

TISSUE(S): Wing Disc

DISEASE(S): Diamond-blackfan Anemia

SUBMITTER: Joanna Kirkpatrick

LAB HEAD: Jean-Paul Vincent

PROVIDER: PXD023021 | Pride | 2021-01-14

REPOSITORIES: Pride

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