Mechanistic origin of cell-size control and homeostasis in bacteria

Abstract

ABSTRACTEvolutionarily divergent bacteria share a common phenomenological strategy for cell-size homeostasis under steady-state conditions. In the presence of inherent physiological stochasticity, cells following this “adder” principle gradually return to their steady-state size by adding a constant volume between birth and division regardless of their size at birth. However, the mechanism of the adder has been unknown despite intense efforts. In this work, we show that the adder is a direct consequence of two general processes in biology: (1) threshold -- accumulation of initiators and precursors required for cell division to a respective fixed number, and (2) balanced biosynthesis -- maintenance of their production proportional to volume growth. This mechanism is naturally robust to static growth inhibition, but also allows us to “reprogram” cell-size homeostasis in a quantitatively predictive manner in both Gram-negativeEscherichia coliand Gram-positiveBacillus subtilis. By generating dynamic oscillations in the concentration of the division protein FtsZ, we were able to oscillate cell size at division and systematically break the adder. In contrast, periodic induction of replication initiator protein DnaA caused oscillations in cell size at initiation, but did not alter division size or the adder. Finally, we were able to restore the adder phenotype in slow-growingE. coli, the only known steady-state growth condition whereinE. colisignificantly deviates from the adder, by repressing active degradation of division proteins. Together these results show that cell division and replication initiation are independently controlled at the gene-expression level, and that division processes exclusively drive cell-size homeostasis in bacteria.HIGHLIGHTSThe adder requires accumulation of division proteins to a threshold for division.The adder requires constant production of division proteins during cell elongation.InE. coliandB. subtilis, initiation and division are independently controlled.InE. coliandB. subtilis, cell division exclusively drives size homeostasis.GRAPHICAL ABSTRACTeTOC BlurbSi and Le Treutet al. show that cell-size homeostasis in bacteria is exclusively driven by accumulation of division proteins to a threshold and their balanced biosynthesis during cell elongation. This mechanistic insight allowed them to reprogram cell-size homeostasis in bothE. coliandB. subtilis. Evolutionary implications are discussed.