Abstract
Many signaling circuits face a fundamental tradeoff between accelerating
their response speed while maintaining final levels below a cytotoxic
threshold. Here, we describe a transcriptional circuitry that
dynamically converts signaling inputs into faster rates without
amplifying final equilibrium levels. Using time-lapse microscopy, we
find that transcriptional activators accelerate human cytomegalovirus
(CMV) gene expression in single cells without amplifying steady-state
expression levels, and this acceleration generates a significant
replication advantage. We map the accelerator to a highly
self-cooperative transcriptional negative-feedback loop (Hill
coefficient similar to 7) generated by homomultimerization of the
virus's essential transactivator protein IE2 at nuclear PML bodies.
Eliminating the IE2-accelerator circuit reduces transcriptional strength
through mislocalization of incoming viral genomes away from PML bodies
and carries a heavy fitness cost. In general, accelerators may provide a
mechanism for signal-transduction circuits to respond quickly to
external signals without increasing steady-state levels of potentially
cytotoxic molecules.
