Does ribosome composition maximize growth rate? The role of RNA instability

Abstract

Ribosomes are protein synthesis machines that are central to cellular self-fabrication, and the synthesis time of a ribosome places an upper bound on growth rate. While most cellular enzymes are proteins, ribosomes consist of 1/3 protein and 2/3 RNA (in E. coli). Recent research suggests that ribosome composition arises from a trade-off between two "autocatalytic loops", ribosomal protein and RNA polymerase synthesis, respectively. In this study, we develop a (coarse-grained) mechanistic model of a self-fabricating cell and validate it under various growth conditions. Using resource balance analysis (RBA), we examine how the maximum growth rate varies with ribosome composition, assuming that all kinetic parameters remain independent of ribosome composition. Our model highlights the importance of RNA instability. If we neglect it, RNA synthesis is always "cheaper" than protein synthesis, leading to an RNA-only ribosome at maximum growth rate. However, when we account for RNA turnover, we find that a mixed ribosome composed of RNA and proteins maximizes growth rate. To account for RNA turnover, we explore two scenarios regarding the activity of RNases. In (a) degradation is proportional to RNA content, whereas in (b) ribosomal proteins cooperatively mitigate RNA instability by protecting it from misfolding and subsequent degradation. In both cases, an increase in ribosomal protein content raises protein synthesis costs while reducing RNA turnover costs. This leads to a mixed ribosome composed of RNA and proteins. However, only in scenario (b), where we consider the cooperative protection of ribosomal RNA by proteins, our model predictions are in qualitative agreement with experimental data under different growth conditions. Our research offers new mechanistic insights into ribosome biogenesis and evolution. Furthermore, it paves the way for understanding the protein-rich ribosome composition found in archaea and mitochondria.