An endogenous accelerator for viral gene expression confers a fitness advantage

Melissa W. Teng, Cynthia Bolovan-Fritts, Roy David 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
Externally publishedYes

Fingerprint

Trans-Activators
Viral Genes
Viral Genome
Cytomegalovirus
Gene expression
Particle accelerators
Microscopy
Signal Transduction
Viruses
Gene Expression
Costs and Cost Analysis
Networks (circuits)
Signal transduction
Proteins
Microscopic examination
Genes
Feedback
Molecules
Costs

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

An endogenous accelerator for viral gene expression confers a fitness advantage. / Teng, Melissa W.; Bolovan-Fritts, Cynthia; Dar, Roy David; Womack, Andrew; Simpson, Michael L.; Shenk, Thomas; Weinberger, Leor S.

In: Cell, Vol. 151, No. 7, 21.12.2012, p. 1569-1580.

Research output: Contribution to journalArticle

Teng, MW, Bolovan-Fritts, C, Dar, RD, Womack, A, Simpson, ML, Shenk, T & Weinberger, LS 2012, 'An endogenous accelerator for viral gene expression confers a fitness advantage', Cell, vol. 151, no. 7, pp. 1569-1580. https://doi.org/10.1016/j.cell.2012.11.051
Teng MW, Bolovan-Fritts C, Dar RD, Womack A, Simpson ML, Shenk T et al. An endogenous accelerator for viral gene expression confers a fitness advantage. Cell. 2012 Dec 21;151(7):1569-1580. https://doi.org/10.1016/j.cell.2012.11.051
Teng, Melissa W. ; Bolovan-Fritts, Cynthia ; Dar, Roy David ; Womack, Andrew ; Simpson, Michael L. ; Shenk, Thomas ; Weinberger, Leor S. / An endogenous accelerator for viral gene expression confers a fitness advantage. In: Cell. 2012 ; Vol. 151, No. 7. pp. 1569-1580.
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