Abstract
To achieve maximal growth, cells must manage a massive economy of ribosomal proteins (r-proteins) and RNAs (rRNAs), which are required to produce thousands of new ribosomes every minute. Although ribosomes are essential in all cells, disruptions to ribosome biogenesis lead to heterogeneous phenotypes. Here, we modeled these perturbations in Saccharomyces cerevisiae and show that challenges to ribosome biogenesis result immediately in acute loss of proteostasis (protein folding homeostasis). Imbalances in the synthesis of r-proteins and rRNAs lead to the rapid aggregation of newly synthesized orphan r-proteins and compromise essential cellular processes. In response, proteostasis genes are activated by an Hsf1-dependent stress response pathway that is required for recovery from r-protein assembly stress. Importantly, we show that exogenously bolstering the proteostasis network increases cellular fitness in the face of challenges to ribosome assembly, demonstrating the direct contribution of orphan r-proteins to cellular phenotypes. Our results highlight ribosome assembly as a linchpin of cellular homeostasis, representing a key proteostasis vulnerability for rapidly proliferating cells that may be compromised by diverse genetic, environmental, and xenobiotic conditions that generate orphan r-proteins.
