How to save a bacterial ribosome in times of stress.

Biogenesis of ribosomes is one of the most cost- and resource-intensive processes in all living cells. In bacteria, ribosome biogenesis is rate-limiting for growth and must be tightly coordinated to yield maximum fitness of the cells. Since bacteria are continuously facing environmental changes and stress conditions, they have developed sophisticated systems to sense and regulate their nutritional status. Amino acid starvation leads to the synthesis and accumulation of the nucleotide-based second messengers ppGpp and pppGpp [(p)ppGpp], which in turn function as central players of a pleiotropic metabolic adaptation mechanism named the stringent response. Here, we review our current knowledge on the multiple roles of (p)ppGpp in the stress-related modulation of the prokaryotic protein biosynthesis machinery with the ribosome as its core constituent. The alarmones ppGpp/pppGpp act as competitors of their GDP/GTP counterparts, to affect a multitude of ribosome-associated P-loop GTPases involved in the translation cycle, ribosome biogenesis and hibernation. A similar mode of inhibition has been found for the GTPases of the proteins involved in the SRP-dependent membrane-targeting machinery present in the periphery of the ribosome. In this sense, during stringent conditions, binding of (p)ppGpp restricts the membrane insertion and secretion of proteins. Altogether, we highlight the enormously resource-intensive stages of ribosome biogenesis as a critical regulatory hub of the stringent response that ultimately tunes the protein synthesis capacity and consequently the survival of the cell.