Abstract
Cellular networks are intrinsically subject to stochastic fluctuations, but analysis of the resulting noise remained largely limited to gene expression. The pathway controlling chemotaxis of Escherichia coli provides one example where posttranslational signaling noise has been deduced from cellular behavior. This noise was proposed to result from stochasticity in chemoreceptor methylation, and it is believed to enhance environment exploration by bacteria. Here we combined single-cell FRET measurements with analysis based on the fluctuation-dissipation theorem (FDT) to characterize origins of activity fluctuations within the chemotaxis pathway. We observed surprisingly large methylation-independent thermal fluctuations of receptor activity, which contribute to noise comparably to the energy-consuming methylation dynamics. Interactions between clustered receptors involved in amplification of chemotactic signals are also necessary to produce the observed large activity fluctuations. Our work thus shows that the high response sensitivity of this cellular pathway also increases its susceptibility to noise, from thermal and out-of-equilibrium processes.
Highlights
It is well established that cellular processes are intrinsically stochastic and prone to fluctuations [1,2,3]
Noise that arises in 32 cellular networks at the posttranslational level remains much less characterized. Such noise is expected to be ubiquitous, e.g., in signaling networks, it was mostly observed indirectly through its effects on gene expression or cell behavior [1, 3]. Chemotaxis of Escherichia coli, a bacterial model for signal transduction, previously provided one example where signaling noise has been predicted based on analyses of cell motility and flagellar rotation [9,10,11,12,13,14,15]
In previous studies where this assay was applied to investigate chemotactic signaling in E. coli populations [18, 24, 26, 42, 44, 50,51,52,53,54,55,56,57,58,59,60], bacteria expressing the FRET pair were immobilized in a flow chamber and fluorescent signals were collected using photon counters from an area containing several hundred cells [50]
Summary
It is well established that cellular processes are intrinsically stochastic and prone to fluctuations [1,2,3]. Since receptor methylation increases the activity of the chemosensory complexes, these changes gradually compensate for the effects of both attractant and repellent stimulation via a negative feedback loop [20,21,22] This enables bacteria to robustly maintain an intermediate steady-state activity of CheA, and the level of CheY phosphorylation and frequency of cell tumbles, even in the presence of steady background stimulation. Subsequent theoretical analyses suggested that such behavioral fluctuations might provide physiological benefit, by enhancing environmental exploration [10, 36,37,38,39,40] Another distinctive feature of the bacterial chemotaxis pathway is the clustering of chemoreceptors in large signaling arrays, formed through a complex network of interactions between trimers of receptor dimers, CheA and CheW [16].
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