A theoretical steady state analysis indicates that induction of Escherichia coli glnALG operon can display all-or-none behavior

Abstract

The nitrogen starvation response in Escherichia coli is characterized by the enhanced expression of Ntr regulon, comprising hundreds of genes including the one coding for nitrogen-assimilating glutamine synthetase (GS) enzyme. The biosynthesis and activity of GS is regulated mainly by nitrogen and carbon levels in the cell and monitored by three functionally separable interconnected modules. Here, we present the steady-state modular analysis of this intricate network made up of a GS bicyclic closed-loop cascade, a NRII-NRI two-component system, and an autoregulated glnALG operon encoding genes for GS, NRII, and NRI. Our simulation results indicate that the transcriptional output of glnALG operon is discrete and switch-like, whereas the activation of transcription factor NRI is graded, and the inactivation of GS is moderately ultrasensitive to input stimulus glutamine. The autoregulation of the NRII-NRI two-component system was found to be essential for the all-or-none induction of the glnALG operon. Furthermore, we show that the autoregulated two-component system modulates the total active GS by delineating the GS activity from its biosynthetic regulation. Our analysis indicates that the exclusive relationship between GS activity and its synthesis is brought about by the autoregulated two-component system. The modularity of the network endows the system to respond differently to nitrogen depending on the carbon status of the cell. Through a system-level quantification, we conclude that the discrete switch-like transcriptional response of the E. coli glnALG operon to nutrient starvation prevents the premature initiation of transcription and may represent the desperate attempt by the cell to survive in limiting conditions.