Coordinate Regulation of Ribosome and tRNA Biogenesis Controls Hypoxic Injury and Translation

The translation machinery is composed of a myriad of proteins and RNAs whose levels must be coordinated to efficiently produce proteins without wasting energy or substrate. However, protein synthesis is clearly not always perfectly tuned to its environment, as disruption of translation machinery components can lengthen lifespan and stress survival. While much has been learned from bacteria and yeast about translational regulation, much less is known in metazoans. In a screen for mutations protecting C. elegans from hypoxic stress, we isolated multiple genes impacting protein synthesis: a ribosomal RNA helicase gene, tRNA biosynthesis genes, and a gene controlling amino acid availability. To define better the mechanisms by which these genes impact protein synthesis, we performed a second screen for suppressors of the conditional developmental arrest phenotype of the RNA helicase mutant and identified genes involved in ribosome biogenesis. Surprisingly, these suppressor mutations restored normal hypoxic sensitivity and protein synthesis to the tRNA biogenesis mutants, but not to the mutant reducing amino acid uptake. Proteomic analysis demonstrated that reduced tRNA biosynthetic activity produces a selective homeostatic reduction in ribosomal subunits, thereby offering a mechanism for the suppression results. Our study uncovers an unrecognized higher-order-translation regulatory mechanism in a metazoan whereby ribosome biogenesis genes communicate with genes controlling tRNA abundance matching the global rate of protein synthesis with available resources. [Display omitted] •Enhanced ribosome biogenesis restores translation despite reduced tRNA biogenesis•Reduced tRNA biogenesis can selectively reduce ribosomal proteins•This feedback mechanism controls both protein synthesis and hypoxic sensitivity•The translation machinery is crucial to hypoxic sensitivity In a screen in the nematode C. elegans for mutants that are resistant to hypoxic cellular injury, Itani et al. isolate mutations in multiple genes in the translation machinery. Subsequent genetic and proteomic experiments lead to our serendipitous discovery of a feedback mechanism between tRNA and ribosome biogenesis.