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An Endogenous Accelerator for Viral Gene Expression Confers a Fitness Advantage...

Publication Type
Journal
Journal Name
Cell
Publication Date
Page Numbers
1569 to 1580
Volume
151
Issue
7

Signal transduction circuits have long been known to differentiate between signals by amplifying inputs to different levels. Here, we describe a novel transcriptional circuitry that dynamically converts greater input levels into faster rates, without increasing the final equilibrium level (i.e. a rate amplifier). We utilize time-lapse microscopy to study human herpesvirus (cytomegalovirus) infection of live cells in real time. Strikingly, our results show that transcriptional activators accelerate viral gene expression in single cells without amplifying the steady-state levels of gene products in these cells. Experiment and modeling show that rate amplification operates by dynamically manipulating the traditional ‘gain-bandwidth’ feedback relationship from electrical circuit theory to convert greater input levels into faster rates, and is driven by highly self-cooperative transcriptional feedback encoded by the virus’s essential transactivator, IE2. This transcriptional rate-amplifier provides a significant fitness advantage for the virus and for minimal synthetic circuits. In general, rate-amplifiers may provide a mechanism for signal-transduction circuits to respond quickly to external signals without increasing steady-state levels of potentially cytotoxic molecules.