An endogenous accelerator for viral gene expression confers a fitness advantage

Melissa W. Teng, Cynthia Bolovan-Fritts, Roy D. Dar, Andrew Womack, Michael L. Simpson, Thomas Shenk, Leor S. Weinberger

Research output: Contribution to journalArticle

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.

Original languageEnglish (US)
Pages (from-to)1569-1580
Number of pages12
JournalCell
Volume151
Issue number7
DOIs
StatePublished - Dec 21 2012

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ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)

Cite this

Teng, M. W., Bolovan-Fritts, C., Dar, R. D., Womack, A., Simpson, M. L., Shenk, T., & Weinberger, L. S. (2012). An endogenous accelerator for viral gene expression confers a fitness advantage. Cell, 151(7), 1569-1580. https://doi.org/10.1016/j.cell.2012.11.051