An endogenous accelerator for viral gene expression confers a fitness advantage

Cell. 2012 Dec 21;151(7):1569-80. doi: 10.1016/j.cell.2012.11.051.

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 ∼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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • Cytomegalovirus / genetics*
  • Cytomegalovirus / physiology
  • Cytomegalovirus Infections / virology*
  • Feedback, Physiological
  • Fibroblasts / virology
  • Gene Expression Regulation, Viral
  • Gene Regulatory Networks*
  • Genetic Fitness*
  • Humans
  • Immediate-Early Proteins / metabolism
  • Inclusion Bodies, Viral / metabolism
  • Time-Lapse Imaging
  • Trans-Activators / metabolism
  • Transcriptional Activation
  • Virus Replication

Substances

  • IE2 protein, Cytomegalovirus
  • Immediate-Early Proteins
  • Trans-Activators