Queueing up for enzymatic processing: correlated signaling through coupled degradation

High‐throughput technologies have led to the generation of complex wiring diagrams as a post‐sequencing paradigm for depicting the interactions between vast and diverse cellular species. While these diagrams are useful for analyzing biological systems on a large scale, a detailed understanding of the molecular mechanisms that underlie the observed network connections is critical for the further development of systems and synthetic biology. Here, we use queueing theory to investigate how ‘waiting lines’ can lead to correlations between protein ‘customers’ that are coupled solely through a downstream set of enzymatic ‘servers’. Using the E. coli ClpXP degradation machine as a model processing system, we observe significant cross‐talk between two networks that are indirectly coupled through a common set of processors. We further illustrate the implications of enzymatic queueing using a synthetic biology application, in which two independent synthetic networks demonstrate synchronized behavior when common ClpXP machinery is overburdened. Our results demonstrate that such post‐translational processes can lead to dynamic connections in cellular networks and may provide a mechanistic understanding of existing but currently inexplicable links. Overloaded enzymatic processes are shown to create indirect coupling between upstream components in cellular networks. This has important implications for the design of synthetic biology devices and for our understanding of currently inexplicable links within endogenous biological systems. Synopsis Overloaded enzymatic processes are shown to create indirect coupling between upstream components in cellular networks. This has important implications for the design of synthetic biology devices and for our understanding of currently inexplicable links within endogenous biological systems. Queueing theory is used to investigate how ‘waiting lines’ can lead to correlations between proteins that are coupled solely through a downstream set of common enzymes. The Escherichia coli ClpXP degradation machinery serves as a model processing system, and significant cross‐talk arises between two independent networks that involve proteins tagged for removal by this shared enzymatic process. Computational modeling demonstrates how a native stress response network implements coupling due to queueing, helping to confer the rapid build‐up of the master stress regulator when needed and its rapid removal from the system when stress‐free conditions