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Multisite phosphorylation regulates phenotypic variability in antibiotic tolerance

Elizabeth Libby, View ORCID ProfileShlomi Reuveni, View ORCID ProfileJonathan Dworkin
doi: https://doi.org/10.1101/315085
Elizabeth Libby
Harvard Medical School;
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Shlomi Reuveni
Tel Aviv University;
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Jonathan Dworkin
Columbia University
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  • For correspondence: jonathan.dworkin@columbia.edu
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Abstract

Isogenic populations of cells exhibit phenotypic variability that has specific physiological consequences. For example, individual bacteria can differ in their sensitivity to an antibiotic, but whether this variability is regulated or an unavoidable consequence of stochastic fluctuations is unclear. We observed that a bacterial stress response gene, the (p)ppGpp synthetase sasA, exhibits high levels of extrinsic noise in expression, suggestive of a regulatory process. We traced this variability to the convergence of two signaling systems that together control an event largely unexplored in bacteria, the multisite phosphorylation of a transcription factor. We found that this regulatory intersection is crucial for controlling the appearance of outliers, rare cells with unusually high levels of sasA expression. Additionally, by examining the full distributions of gene expression we calculated the importance of multisite phosphorylation in setting the relative abundance of cells with a given a level of SasA. We then created a predictive model for the probability of a given cell surviving antibiotic treatment as a function of sasA expression. Therefore, our data show that multisite phosphorylation can be used to strongly regulate bacterial physiology and sensitivity to antibiotic treatment.

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The copyright holder for this preprint is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. All rights reserved. No reuse allowed without permission.
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Posted May 04, 2018.
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Multisite phosphorylation regulates phenotypic variability in antibiotic tolerance
Elizabeth Libby, Shlomi Reuveni, Jonathan Dworkin
bioRxiv 315085; doi: https://doi.org/10.1101/315085
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Multisite phosphorylation regulates phenotypic variability in antibiotic tolerance
Elizabeth Libby, Shlomi Reuveni, Jonathan Dworkin
bioRxiv 315085; doi: https://doi.org/10.1101/315085

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