Overcoming the Cost of Positive Autoregulation by Accelerating the Response with a Coupled Negative Feedback

Abstract

Summary: A fundamental trade-off between rapid response and optimal expression of genes below cytotoxic levels exists for many signaling circuits, particularly for positively autoregulated systems with an inherent response delay. Here, we describe a regulatory scheme in the E. coli PhoB-PhoR two-component system, which overcomes the cost of positive feedback and achieves both fast and optimal steady-state response for maximal fitness across different environments. Quantitation of the cellular activities enables accurate modeling of the response dynamics to describe how requirements for optimal protein concentrations place limits on response speed. An observed fast response that exceeds the limit led to the prediction and discovery of a coupled negative autoregulation, which allows fast gene expression without increasing steady-state levels. We demonstrate the fitness advantages for the coupled feedbacks in both dynamic and stable environments. Such regulatory schemes offer great flexibility for accurate control of gene expression levels and dynamics upon environmental changes. : Positive autoregulation of transcription produces a delayed response. Gao and Stock describe the limit of response delay caused by requirements of optimal protein levels in the PhoBR two-component system. Coupled negative autoregulation is discovered to allow a strong promoter for fast response without incurring cost of increasing protein expression levels. Keywords: autoregulation, transcription dual regulation, positive feedback, negative feedback, coupled feedback, two-component system, fitness, response dynamics, DNA-binding affinity, promoter architecture