RpS19a depletion alters the hematopoietic translatome to drive tissue overgrowth

Despite ribosomal protein loss correlating with increased tumor predisposition, direct mechanisms for the counterintuitive oncogenic effect of ribosomal protein depletion have not been reported. We used genetic models to investigate ribosomal protein S19a (RpS19a) depletion in the Drosophila blood organ, the lymph gland. Intriguingly, we demonstrate that RpS19a depletion directly drives excess proliferation and tissue overgrowth. Proteomic and differential translation analysis of RpS19a-depleted cells revealed altered stoichiometry of translation initiation factors and increased association of ribosomes with mRNAs encoding growth-promoting proteins. Furthermore, ribosomes in RpS19a-depleted cells are associated with mRNA encoding dNep1, a putative ribosomal RNA methyltransferase. Although uncharacterized in Drosophila, NEP1 is implicated in ribosomal RNA methylation and ribosome stability in yeast and humans, and its mutations underpin the ribosomopathy Bowen-Conradi syndrome. The RpS19a knockdown phenotype is suppressed by dNep1 co-depletion, altogether suggesting that dNep1 enables assembly of pro-proliferative ribosomes essential for blood lineage overgrowth driven by ribosomal protein loss.