Tight Control Over Cytoplasmic and Membrane Protein Densities Defines Regulation of Cell Geometry in Escherichia coli*

The interplay between gene expression, macromolecular composition, and cell size control has been a central topic in the study of microbial physiology for the better part of a century. However, we lack a mechanistic understanding of how cells so tightly coordinate biosynthesis and cell size control across diverse environments. In this work, we present a simple theory of cellular resource allocation that quantitatively predicts how rod-shaped bacterial cells control their surface-area-to-volume across a broad range of growth conditions. Central to this theory is a biochemical constraint that the protein density within the cell membranes and the macromolecular density within the cell cytoplasm are strictly controlled and kept at a constant ratiometric value. As a result, this theory predicts a sublinear scaling relationship between the cellular surface-to-volume ratio and ribosome content, linking empirical “growth laws” in a predictive manner.  We compare these predictions to a broad array of literature data and our own measurements in E. coli. Furthermore, we test this theory through genetic perturbations of cellular ribosome content and demonstrate that cell size and bulk growth rate can be effectively decoupled, challenging a long-held hypothesis that the former is set by the latter.