title: An endogenous accelerator for viral gene expression confers a fitness advantage.
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.
authors.affiliation: The Gladstone Institutes, San Francisco, CA 94158, USA.
authors.forename: Melissa W
authors.initials: MW
authors.lastname: Teng
authors.forename: Cynthia
authors.initials: C
authors.lastname: Bolovan-Fritts
authors.forename: Roy D
authors.initials: RD
authors.lastname: Dar
authors.forename: Andrew
authors.initials: A
authors.lastname: Womack
authors.forename: Michael L
authors.initials: ML
authors.lastname: Simpson
authors.forename: Thomas
authors.initials: T
authors.lastname: Shenk
authors.forename: Leor S
authors.initials: LS
authors.lastname: Weinberger
mesh_terms: D003587:Cytomegalovirus / Q000235:genetics* / Q000502:physiology; D003586:Cytomegalovirus Infections / Q000821:virology*; D025461:Feedback, Physiological; D005347:Fibroblasts / Q000821:virology; D015967:Gene Expression Regulation, Viral; D053263:Gene Regulatory Networks; D056084:Genetic Fitness; D006801:Humans; D017874:Immediate-Early Proteins / Q000378:metabolism; D007181:Inclusion Bodies, Viral / Q000378:metabolism; D059008:Time-Lapse Imaging; D015534:Trans-Activators / Q000378:metabolism; D015533:Transcriptional Activation; D014779:Virus Replication
chemical_list: C069186:IE2 protein, Cytomegalovirus; D017874:Immediate-Early Proteins; D015534:Trans-Activators