Convergent nuclear proteostasis alterations across 40S ribosomal protein deficiencies

Defects in ribosome biogenesis cause ribosomopathies, but the pathogenic role of malformed preribosomes remains unclear. Using preribosome fractionation, live-cell and confocal microscopy, and automated imaging screens, we tracked abortive preribosomes following depletion of the 33 small-subunit ribosomal proteins (RPSs). We found that all RPS deficiencies lead to accumulation of nucleolar preribosome materials in the nucleoplasm, regardless of the affected 40S subunit maturation stage. These aberrant particles appear as dispersed complexes or persistent aggregates arising during nucleolar reassembly in late mitosis. Although nucleolar morphology remains largely intact, their accumulation impairs recycling of nucleolar factors and disrupts nucleolar-nucleoplasmic proteostasis. Distinct RPS deficiencies produce different preribosome behaviors, indicating maturation-specific properties. Notably, depletion of RPS19, the protein encoded by the most frequently mutated gene in Diamond-Blackfan anemia, causes particularly severe defects. Our findings identify nucleoplasmic preribosome aggregation and dispersion as common consequences of RPS deficits and potential contributors to 40S ribosomopathy pathogenesis.