Ribosome biogenesis and homeostasis: in the front line to cope with cellular stress

Cells must continuously adapt to both internal and environmental stresses by finely tuning their molecular and metabolic activities. One of the most regulated energy-consuming processes is ribosome biogenesis, essential for gene expression modulation. While the focus is often on the regulation of this process during growth and proliferation, this review incorporates exciting recent findings describing molecular checkpoints and signaling that converge to and derive from ribosomes under stress conditions, in both yeast and mammals. Special emphasis is placed on the roles of transcription factors and ribosome-binding proteins in repressing ribosomal gene expression and pre-ribosome maturation, as well as on the translational reprogramming that occurs through mechanisms such as eIF2α phosphorylation, specialized ribosome, and ribosome hibernation. In addition, we examine the interplay between ribosome homeostasis and key signaling cascades that ultimately determine cell fate. We especially focus on regulations mediated by conserved signaling pathways such as the Integrated Stress Response, the Ribotoxic Stress Response and the AMP-activated protein kinase cascade. Lastly, we discuss the p53 signaling pathway as a central integrator of nucleolar stress, linking ribosome biogenesis impairment to critical cell fate decisions, such as cell cycle arrest, senescence, or apoptosis. Together, these insights provide a comprehensive overview of stress-response integration onto ribosomes and underscore the central role of ribosome homeostasis in cellular adaptation across the eukaryotic systems.