Cellular perception of growth rate and the mechanistic origin of bacterial growth law

Many cellular activities in bacteria are organized according to their growth rate. The notion that ppGpp measures the cell’s growth rate is well accepted in the field of bacterial physiology. However, despite decades of interrogation and the identification of multiple molecular interactions that connects ppGpp to some aspects of cell growth, we lack a system-level, quantitative picture of how this alleged “measurement” is performed. Through quantitative experiments, we show that the ppGpp pool responds inversely to the rate of translational elongation in Escherichia coli. Together with its roles in inhibiting ribosome biogenesis and activity, ppGpp closes a key regulatory circuit that enables the cell to perceive and control the rate of its growth across conditions. The celebrated linear growth law relating the ribosome content and growth rate emerges as a consequence of keeping a supply of ribosome reserves while maintaining elongation rate in slow growth conditions. Further analysis suggests the elongation rate itself is detected by sensing the ratio of dwelling and translocating ribosomes, a strategy employed to collapse the complex, high-dimensional dynamics of the molecular processes underlying cell growth to perceive the physiological state of the whole.