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^1,2,3. 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.

核糖体是合成活细胞所有蛋白质的多组分分子机器。因此，大多数编码核糖体蛋白质成分的基因都是必需的。基因剂量的减少通常是可行的，尽管是有害的，并且与人类综合症相关，这些综合症统称为核糖病^1,2,3。这些病理学的细胞生物学基础仍不清楚。在这里，我们在果蝇中模拟人类核糖病，并在所得动物中发现广泛的细胞凋亡和细胞应激。正如合理预期的那样，这并不是由蛋白质合成不足引起的。相反，核糖体蛋白缺乏会引发蛋白毒性应激，我们认为这是由错误折叠蛋白的积累导致的，这些蛋白压倒了蛋白降解机制。我们发现抑制综合应激反应⁴或自噬会增加核糖体蛋白缺乏造成的危害，这表明这些活动可能具有细胞保护作用。TOR 活性的抑制（可减少核糖体蛋白质的产生、减慢蛋白质合成并刺激自噬⁵）可减少我们的核糖体病模型中的蛋白毒性应激。刺激自噬的干预措施与加强蛋白质质量控​​制的方法相结合，可以构成此类疾病治疗策略的基础。