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Coordination of bacterial proteome with metabolism by cyclic AMP signalling

Nature volume 500, pages 301–306 (2013)Cite this article

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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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Figure 1: Catabolic and biosynthetic gene expression under nutrient limitations.
Figure 2: Proteome fractions and the partition model.
Figure 3: Transient repression by metabolic precursors.
Figure 4: Mechanism of cAMP-dependent signalling.

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References

  1. Laub, M. T. & Goulian, M. Specificity in two-component signal transduction pathways. Annu. Rev. Genet. 41, 121–145 (2007)

    Article  CAS  Google Scholar 

  2. Potrykus, K. & Cashel, M. (p)ppGpp: still magical? Annu. Rev. Microbiol. 62, 35–51 (2008)

    Article  CAS  Google Scholar 

  3. Hengge, R. Principles of c-di-GMP signalling in bacteria. Nature Rev. Microbiol. 7, 263–273 (2009)

    Article  CAS  Google Scholar 

  4. Porter, S. L., Wadhams, G. H. & Armitage, J. P. Signal processing in complex chemotaxis pathways. Nature Rev. Microbiol. 9, 153–165 (2011)

    Article  CAS  Google Scholar 

  5. Brent, R. Cell signaling: what is the signal and what information does it carry? FEBS Lett. 583, 4019–4024 (2009)

    Article  CAS  Google Scholar 

  6. Purvis, J. E. et al. p53 dynamics control cell fate. Science 336, 1440–1444 (2012)

    Article  ADS  CAS  Google Scholar 

  7. Hao, N., Budnik, B. A., Gunawardena, J. & O’Shea, E. K. Tunable signal processing through modular control of transcription factor translocation. Science 339, 460–464 (2013)

    Article  ADS  CAS  Google Scholar 

  8. Young, J. W., Locke, J. C. & Elowitz, M. B. Rate of environmental change determines stress response specificity. Proc. Natl Acad. Sci. USA 110, 4140–4145 (2013)

    Article  ADS  CAS  Google Scholar 

  9. Makman, R. S. & Sutherland, E. W. Adenosine 3′,5′-phosphate in Escherichia coli. J. Biol. Chem. 240, 1309–1314 (1965)

    CAS  PubMed  Google Scholar 

  10. Perlman, R. L., De Crombrugghe, B. & Pastan, I. Cyclic AMP regulates catabolite and transient repression in E. coli. Nature 223, 810–812 (1969)

    Article  ADS  CAS  Google Scholar 

  11. Magasanik, B. Catabolite repression. Cold Spring Harb. Symp. Quant. Biol. 26, 249–256 (1961)

    Article  CAS  Google Scholar 

  12. Epps, H. M. & Gale, E. F. The influence of the presence of glucose during growth on the enzymic activities of Escherichia coli: comparison of the effect with that produced by fermentation acids. Biochem. J. 36, 619–623 (1942)

    Article  CAS  Google Scholar 

  13. Neidhardt, F. C. & Magasanik, B. Effect of mixtures of substrates on the biosynthesis of inducible enzymes in Aerobacter aerogenes. J. Bacteriol. 73, 260–263 (1957)

    CAS  PubMed  PubMed Central  Google Scholar 

  14. Kolb, A., Busby, S., Buc, H., Garges, S. & Adhya, S. Transcriptional regulation by cAMP and its receptor protein. Annu. Rev. Biochem. 62, 749–797 (1993)

    Article  CAS  Google Scholar 

  15. Saier, M. H., Jr, Feucht, B. U. & Hofstadter, L. J. Regulation of carbohydrate uptake and adenylate cyclase activity mediated by the enzymes II of the phosphoenolpyruvate: sugar phosphotransferase system in Escherichia coli. J. Biol. Chem. 251, 883–892 (1976)

    CAS  PubMed  Google Scholar 

  16. Deutscher, J., Francke, C. & Postma, P. W. How phosphotransferase system-related protein phosphorylation regulates carbohydrate metabolism in bacteria. Microbiol. Mol. Biol. Rev. 70, 939–1031 (2006)

    Article  CAS  Google Scholar 

  17. Epstein, W., Rothman-Denes, L. B. & Hesse, J. Adenosine 3′:5′-cyclic monophosphate as mediator of catabolite repression in Escherichia coli. Proc. Natl Acad. Sci. USA 72, 2300–2304 (1975)

    Article  ADS  CAS  Google Scholar 

  18. Hogema, B. M. et al. Catabolite repression by glucose 6-phosphate, gluconate and lactose in Escherichia coli. Mol. Microbiol. 24, 857–867 (1997)

    Article  CAS  Google Scholar 

  19. Bettenbrock, K. et al. Correlation between growth rates, EIIACrr phosphorylation, and intracellular cyclic AMP levels in Escherichia coli K-12. J. Bacteriol. 189, 6891–6900 (2007)

    Article  CAS  Google Scholar 

  20. Mandelstam, J. The repression of constitutive beta-galactosidase in Escherichia coli by glucose and other carbon sources. Biochem. J. 82, 489–493 (1962)

    Article  CAS  Google Scholar 

  21. McFall, E. & Magasanik, B. Effects of thymine and of phosphate deprivation on enzyme synthesis in Escherichia coli. Biochim. Biophys. Acta 55, 900–908 (1962)

    Article  CAS  Google Scholar 

  22. Clark, D. J. & Marr, A. G. Studies on the repression of beta-galactosidase in Escherichia coli. Biochim. Biophys. Acta 92, 85–94 (1964)

    CAS  PubMed  Google Scholar 

  23. Ullmann, A., Tillier, F. & Monod, J. Catabolite modulator factor: a possible mediator of catabolite repression in bacteria. Proc. Natl Acad. Sci. USA 73, 3476–3479 (1976)

    Article  ADS  CAS  Google Scholar 

  24. Narang, A. & Pilyugin, S. S. Bacterial gene regulation in diauxic and non-diauxic growth. J. Theor. Biol. 244, 326–348 (2007)

    Article  MathSciNet  CAS  Google Scholar 

  25. Monod, J. The phenomenon of enzymatic adaptation - and its bearings on problems of genetics and cellular differentiation. Growth 11, 223–289 (1947)

    CAS  Google Scholar 

  26. Okada, T. et al. Role of inducer exclusion in preferential utilization of glucose over melibiose in diauxic growth of Escherichia coli. J. Bacteriol. 146, 1030–1037 (1981)

    CAS  PubMed  PubMed Central  Google Scholar 

  27. Inada, T., Kimata, K. & Aiba, H. Mechanism responsible for glucose-lactose diauxie in Escherichia coli: challenge to the cAMP model. Genes Cells 1, 293–301 (1996)

    Article  CAS  Google Scholar 

  28. Müller-Hill, B. The lac Operon: a Short History of a Genetic Paradigm. (de Gruyter, 1996)

    Google Scholar 

  29. Kuhlman, T., Zhang, Z., Saier, M. H., Jr & Hwa, T. Combinatorial transcriptional control of the lactose operon of Escherichia coli. Proc. Natl Acad. Sci. USA 104, 6043–6048 (2007)

    Article  ADS  CAS  Google Scholar 

  30. Wanner, B. L., Kodaira, R. & Neidhardt, F. C. Regulation of lac operon expression: reappraisal of the theory of catabolite repression. J. Bacteriol. 136, 947–954 (1978)

    CAS  PubMed  PubMed Central  Google Scholar 

  31. Kuo, J. T., Chang, Y. J. & Tseng, C. P. Growth rate regulation of lac operon expression in Escherichia coli is cyclic AMP dependent. FEBS Lett. 553, 397–402 (2003)

    Article  CAS  Google Scholar 

  32. Klumpp, S., Zhang, Z. & Hwa, T. Growth rate-dependent global effects on gene expression in bacteria. Cell 139, 1366–1375 (2009)

    Article  Google Scholar 

  33. Scott, M., Gunderson, C. W., Mateescu, E. M., Zhang, Z. & Hwa, T. Interdependence of cell growth and gene expression: origins and consequences. Science 330, 1099–1102 (2010)

    Article  ADS  CAS  Google Scholar 

  34. Reitzer, L. Nitrogen assimilation and global regulation in Escherichia coli. Annu. Rev. Microbiol. 57, 155–176 (2003)

    Article  CAS  Google Scholar 

  35. Kim, M. et al. Need-based activation of ammonium uptake in Escherichia coli. Mol. Syst. Biol. 8, 616 (2012)

    Article  Google Scholar 

  36. Silverstone, A. E., Arditti, R. R. & Magasanik, B. Catabolite-insensitive revertants of lac promoter mutants. Proc. Natl Acad. Sci. USA 66, 773–779 (1970)

    Article  ADS  CAS  Google Scholar 

  37. Schaechter, M., Maaloe, O. & Kjeldgaard, N. O. Dependency on medium and temperature of cell size and chemical composition during balanced growth of Salmonella typhimurium. J. Gen. Microbiol. 19, 592–606 (1958)

    Article  CAS  Google Scholar 

  38. Maaloe, O. in Biological Regulation and Development 487–542 (Plenum, 1979)

    Google Scholar 

  39. Bender, R. A. & Magasanik, B. Regulatory mutations in the Klebsiella aerogenes structural gene for glutamine synthetase. J. Bacteriol. 132, 100–105 (1977)

    CAS  PubMed  PubMed Central  Google Scholar 

  40. Scott, M. & Hwa, T. Bacterial growth laws and their applications. Curr. Opin. Biotechnol. 22, 559–565 (2011)

    Article  CAS  Google Scholar 

  41. Schuetz, R., Zamboni, N., Zampieri, M., Heinemann, M. & Sauer, U. Multidimensional optimality of microbial metabolism. Science 336, 601–604 (2012)

    Article  ADS  CAS  Google Scholar 

  42. Goyal, S., Yuan, J., Chen, T., Rabinowitz, J. D. & Wingreen, N. S. Achieving optimal growth through product feedback inhibition in metabolism. PLOS Comput. Biol. 6, e1000802 (2010)

    Article  ADS  MathSciNet  Google Scholar 

  43. Doucette, C. D., Schwab, D. J., Wingreen, N. S. & Rabinowitz, J. D. α-ketoglutarate coordinates carbon and nitrogen utilization via enzyme I inhibition. Nature Chem. Biol. 7, 894–901 (2011)

    Article  CAS  Google Scholar 

  44. Yan, D., Lenz, P. & Hwa, T. Overcoming fluctuation and leakage problems in the quantification of intracellular 2-oxoglutarate levels in Escherichia coli. Appl. Environ. Microbiol. 77, 6763–6771 (2011)

    Article  CAS  Google Scholar 

  45. Leigh, J. R. Control Theory (The Institution of Electrical Engineers, 2004)

    Book  Google Scholar 

  46. Peterkofsky, A. & Gazdar, C. Escherichia coli adenylate cyclase complex: regulation by the proton electrochemical gradient. Proc. Natl Acad. Sci. USA 76, 1099–1103 (1979)

    Article  ADS  CAS  Google Scholar 

  47. Tyler, B. & Magasanik, B. Physiological basis of transient repression of catabolic enzymes in Escherichia coli. J. Bacteriol. 102, 411–422 (1970)

    CAS  PubMed  PubMed Central  Google Scholar 

  48. Harwood, J. P. & Peterkofsky, A. Glucose-sensitive adenylate cyclase in toluene-treated cells of Escherichia coli B. J. Biol. Chem. 250, 4656–4662 (1975)

    CAS  PubMed  Google Scholar 

Download references

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).

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Author notes

  1. Hiroyuki Okano and Sheng Hui: These authors contributed equally to this work.

Authors and Affiliations

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

    Conghui You, Hiroyuki Okano, Sheng Hui, Minsu Kim & Terence Hwa

  2. Division of Biological Sciences, Section of Molecular Biology, University of California at San Diego, La Jolla, 92093, California, 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, 92093-0374, California, 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, 46202, Indiana, 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.

Corresponding author

Correspondence to Terence Hwa.

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The authors declare no competing financial interests.

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You, C., Okano, H., Hui, S. et al. Coordination of bacterial proteome with metabolism by cyclic AMP signalling. Nature 500, 301–306 (2013). https://doi.org/10.1038/nature12446

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