Article | Published:

Coordination of bacterial proteome with metabolism by cyclic AMP signalling

Nature volume 500, pages 301306 (15 August 2013) | Download Citation

Abstract

The cyclic AMP (cAMP)-dependent catabolite repression effect in Escherichia coli is among the most intensely studied regulatory processes in biology. However, the physiological function(s) of cAMP signalling and its molecular triggers remain elusive. Here we use a quantitative physiological approach to show that cAMP signalling tightly coordinates the expression of catabolic proteins with biosynthetic and ribosomal proteins, in accordance with the cellular metabolic needs during exponential growth. The expression of carbon catabolic genes increased linearly with decreasing growth rates upon limitation of carbon influx, but decreased linearly with decreasing growth rate upon limitation of nitrogen or sulphur influx. In contrast, the expression of biosynthetic genes showed the opposite linear growth-rate dependence as the catabolic genes. A coarse-grained mathematical model provides a quantitative framework for understanding and predicting gene expression responses to catabolic and anabolic limitations. A scheme of integral feedback control featuring the inhibition of cAMP signalling by metabolic precursors is proposed and validated. These results reveal a key physiological role of cAMP-dependent catabolite repression: to ensure that proteomic resources are spent on distinct metabolic sectors as needed in different nutrient environments. Our findings underscore the power of quantitative physiology in unravelling the underlying functions of complex molecular signalling networks.

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Acknowledgements

We are grateful to R. Bender, A. Danchin, P. Geiduschek, J. Ingraham, S. Kustu, W. F. Loomis, A. Narang, J. Rabinowitz, M. H. Saier and members of the Hwa laboratory for valuable comments. This work was supported by the Human Frontiers in Science Program (RGP0022), and by the NSF to T.H. (PHY1058793) and through the Center for Theoretical Biological Physics (PHY0822283).

Author information

Author notes

    • Hiroyuki Okano
    •  & Sheng Hui

    These authors contributed equally to this work.

Affiliations

  1. Department of Physics, University of California at San Diego, La Jolla, California 92093-0374, USA

    • Conghui You
    • , Hiroyuki Okano
    • , Sheng Hui
    • , Minsu Kim
    •  & Terence Hwa
  2. Section of Molecular Biology, Division of Biological Sciences, University of California at San Diego, La Jolla, California 92093 USA

    • Conghui You
    • , Hiroyuki Okano
    • , Zhongge Zhang
    • , Carl W. Gunderson
    •  & Terence Hwa
  3. Center for Theoretical Biological Physics, University of California at San Diego, La Jolla, California 92093-0374 USA

    • Sheng Hui
    •  & Terence Hwa
  4. State Key Laboratory of Protein and Plant Gene Research, College of Life Sciences, Peking University, Beijing 100871, China

    • Yi-Ping Wang
  5. Department of Physics and Center for Synthetic Microbiology, University of Marburg, 35032 Marburg, Germany

    • Peter Lenz
  6. Department of Microbiology and Immunology, Indiana University School of Medicine, Indianapolis, Indiana 46202, USA

    • Dalai Yan

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Contributions

C.Y., D.Y. and T.H. designed the study. C.Y., H.O., S.H., Z.Z. M.K., C.W.G. and D.Y. performed experiments. C.Y., S.H., Y.P.W. and T.H. analysed the data. P.L. and T.H. developed the model. All authors contributed to writing the paper and the supplement.

Competing interests

The authors declare no competing financial interests.

Corresponding author

Correspondence to Terence Hwa.

Supplementary information

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    Supplementary Information

    This file contains Supplementary Materials and Methods, Supplementary Notes, Supplementary Tables 1-19, Supplementary Figures 1-36 and Supplementary References.

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DOI

https://doi.org/10.1038/nature12446

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