title: The dynamic balance of import and export of zinc in Escherichia coli suggests a heterogeneous population response to stress.
abstract: Zinc is essential for life, but toxic in excess. Thus all cells must control their internal zinc concentration. We used a systems approach, alternating rounds of experiments and models, to further elucidate the zinc control systems in Escherichia coli. We measured the response to zinc of the main specific zinc import and export systems in the wild-type, and a series of deletion mutant strains. We interpreted these data with a detailed mathematical model and Bayesian model fitting routines. There are three key findings: first, that alternate, non-inducible importers and exporters are important. Second, that an internal zinc reservoir is essential for maintaining the internal zinc concentration. Third, our data fitting led us to propose that the cells mount a heterogeneous response to zinc: some respond effectively, while others die or stop growing. In a further round of experiments, we demonstrated lower viable cell counts in the mutant strain tested exposed to excess zinc, consistent with this hypothesis. A stochastic model simulation demonstrated considerable fluctuations in the cellular levels of the ZntA exporter protein, reinforcing this proposal. We hypothesize that maintaining population heterogeneity could be a bet-hedging response allowing a population of cells to survive in varied and fluctuating environments.
authors: Medical Mycology Research Center, Chiba University, 1-8-1 Inohana, Chuo-ku, Chiba, Chiba 260-8673, Japan hiroki.takahashi@chiba-u.jp.
authors: Hiroki
authors: H
authors: Takahashi
authors: Graduate School of Biological Science, Nara Institute of Science and Technology, 8916-5, Takayama, Ikoma, Nara 630-0192, Japan.
authors: Taku
authors: T
authors: Oshima
authors: School of Biosciences, The University of Nottingham, Sutton Bonington Campus, Sutton Bonington, Loughborough LE12 5RD, UK.
authors: Jon L
authors: JL
authors: Hobman
authors: School of Biosciences, The University of Nottingham, Sutton Bonington Campus, Sutton Bonington, Loughborough LE12 5RD, UK.
authors: Neil
authors: N
authors: Doherty
authors: School of Biosciences, The University of Nottingham, Sutton Bonington Campus, Sutton Bonington, Loughborough LE12 5RD, UK.
authors: Selina R
authors: SR
authors: Clayton
authors: School of Biosciences, The University of Nottingham, Sutton Bonington Campus, Sutton Bonington, Loughborough LE12 5RD, UK.
authors: Mudassar
authors: M
authors: Iqbal
authors: School of Biosciences, The University of Nottingham, Sutton Bonington Campus, Sutton Bonington, Loughborough LE12 5RD, UK.
authors: Philip J
authors: PJ
authors: Hill
authors: Laboratory of Molecular Medical Microbiology, Department of Biomedical Informatics, Osaka University Graduate School of Medicine, 1-7 Yamadaoka, Suita, Osaka 565-0871, Japan.
authors: Toru
authors: T
authors: Tobe
authors: Graduate School of Biological Science, Nara Institute of Science and Technology, 8916-5, Takayama, Ikoma, Nara 630-0192, Japan.
authors: Naotake
authors: N
authors: Ogasawara
authors: Graduate School of Information Science, Nara Institute of Science and Technology, 8916-5, Takayama, Ikoma, Nara 630-0192, Japan.
authors: Shigehiko
authors: S
authors: Kanaya
authors: School of Biosciences, The University of Nottingham, Sutton Bonington Campus, Sutton Bonington, Loughborough LE12 5RD, UK dov.stekel@nottingham.ac.uk.
authors: Dov J
authors: DJ
authors: Stekel
mesh_terms: D000251:Adenosine Triphosphatases / Q000378:metabolism*; D003198:Computer Simulation; D004926:Escherichia coli / Q000502:physiology*; D029968:Escherichia coli Proteins / Q000378:metabolism; D025461:Feedback, Physiological / Q000502:physiology*; D018869:Heat-Shock Response / Q000502:physiology*; D026901:Membrane Transport Proteins / Q000378:metabolism; D008954:Models, Biological; D015233:Models, Statistical; D015032:Zinc / Q000378:metabolism*
chemical_list: D029968:Escherichia coli Proteins; D026901:Membrane Transport Proteins; C497880:ZupT protein, E coli; D000251:Adenosine Triphosphatases; C109898:Zn(II)-translocating P-type ATPase; D015032:Zinc
keywords: Escherichia coli; bet hedging; mathematical model; statistical inference; stress response; zinc homeostasis