The inverse correlation between robustness and sensitivity to autoregulation in two-component systems

Two-component systems (TCS) are signal transduction systems in bacteria and many other organisms that relay the sensory signal to genetic components. TCS consist of two proteins: a histidine kinase and a response regulator that the histidine kinase activates. This seemingly simple machinery can generate complex regulatory dynamics that enables the level of gene expression that matches the input signal: many TCS response regulators act on their own genes as transcription factors, resulting in a positive autoregulation mechanism. This regulation, in return, modulates the transcription factor activity as a function of the input signal. Positive autoregulation does not necessarily result in positive feedback. Sensitivity to autoregulation is quantified as the output level amplification resulting from the positive autoregulation mechanism. Another structural property of these systems is formally characterized as "robustness": in a robust TCS, the output of the system is solely a function of the input signal. Thus, a robust TCS remains insensitive to fluctuations in the concentrations of its protein components and, this way, maintains the precision in the output transcription factor activity in response to input stimulus. In this paper, we show with a formal model that TCS operate on a spectrum of inverse correlation between robustness and sensitivity to autoregulation. Our model predicts that the modulation by positive autoregulation is a function of loss in TCS robustness, for example, by spontaneous dephosphorylation of the histidine kinase. Consequently, the loss in robustness provides a proportional modulation by positive autoregulation to widen the response range with a scaled amplification of the output. At the other end of the spectrum, in the presence of a strictly robust TCS machinery, amplification of the transcription factor activity by autoregulation is diminished. We show that our results are in agreement with published experimental results. Our results suggest that these TCS evolve to converge at a trade-off between robustness and positive autoregulation.