Skip to main content
SpringerLink
Log in

Mathematical Modelling of the Sporulation-Initiation Network in Bacillus Subtilis Revealing the Dual Role of the Putative Quorum-Sensing Signal Molecule PhrA

  • Original Article
  • Published:
Bulletin of Mathematical Biology Aims and scope Submit manuscript

Abstract

Bacillus subtilis cells may opt to forgo normal cell division and instead form spores if subjected to certain environmental stimuli, for example nutrient deficiency or extreme temperature. The resulting spores are extremely resilient and can survive for extensive periods of time, importantly under particularly harsh conditions such as those mentioned above. The sporulation process is highly time and energy consuming and essentially irreversible. The bacteria must therefore ensure that this route is only undertaken under appropriate circumstances. The gene regulation network governing sporulation initiation accordingly incorporates a variety of signals and is of significant complexity. We present a model of this network that includes four of these signals: nutrient levels, DNA damage, the products of the competence genes, and cell population size. Our results can be summarised as follows: (i) the model displays the correct phenotypic behaviour in response to these signals; (ii) a basal level of sda expression may prevent sporulation in the presence of nutrients; (iii) sporulation is more likely to occur in a large population of cells than in a small one; (iv) finally, and of most interest, PhrA can act simultaneously as a quorum-sensing signal and as a timing mechanism, delaying sporulation when the cell has damaged DNA, possibly thereby allowing the cell time to repair its DNA before forming a spore.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Similar content being viewed by others

References

  • Asai, K., Kawamura, F., Yoshikawa, H., Takahashi, H., 1995. Expression of kinA and accumulation of σ H at the onset of sporulation in Bacillus subtilis. J. Bacteriol. 177, 6679–6683.

    Google Scholar 

  • Auchtung, J.M., Lee, C.A., Grossman, A.D., 2006. Modulation of the ComA-dependent quorum response in Bacillus subtilis by multiple Rap proteins and Phr peptides. J. Bacteriol. 188, 5273–5285.

    Article  Google Scholar 

  • Bai, U., Lewandowski, M., Dubnau, E., Smith, I., 1990. Temporal regulation of the Bacillus subtilis early sporulation gene spo0F. J. Bacteriol. 172, 5432–5439.

    Google Scholar 

  • Bai, U., Mandic-Mulec, I., Smith, I., 1993. SinI modulates the activity of SinR, a developmental switch protein of Bacillus subtilis, by protein-protein interaction. Genes Dev. 7, 139–148.

    Article  Google Scholar 

  • Benson, L.M., Vaughn, J.L., Strauch, M.A., Bobay, B.G., Thompson, R., Naylor, S., Cavanagh, J., 2002. Macromolecular assembly of the transition state regulator AbrB in its unbound and complexed states probed by microelectrospray ionization mass spectrometry. Anal. Biochem. 306, 222–227.

    Article  Google Scholar 

  • Bischofs, I.B., Hug, J.A., Liu, A.W., Wolf, D.M., Arkin, A.P., 2009. Complexity in bacterial cell-cell communication: quorum signal integration and subpopulation signaling in the Bacillus subtilis phosphorelay. Proc. Natl. Acad. Sci. USA 106, 6459–6464.

    Article  Google Scholar 

  • Blagova, E.V., Levdikov, V.M., Tachikawa, K., Sonenshein, A.L., Wilkinson, A.J., 2003. Crystallization of the GTP-dependent transcriptional regulator CodY from Bacillus subtilis. Acta Crystallogr. D 59, 155–157.

    Article  Google Scholar 

  • Bongiorni, C., Ishikawa, S., Stephenson, S., Ogasawara, N., Perego, M., 2005. Synergistic regulation of competence development in Bacillus subtilis by two Rap-Phr systems. J. Bacteriol. 187, 4353–4361.

    Article  Google Scholar 

  • Burbulys, D., Trach, K.A., Hoch, J.A., 1991. Initiation of sporulation in Bacillus subtilis is controlled by a multicomponent phosphorelay. Cell 64, 545–552.

    Article  Google Scholar 

  • Burkholder, W.F., Kurtser, I., Grossman, A.D., 2001. Replication initiation proteins regulate a developmental checkpoint in Bacillus subtilis. Cell 104, 269–279.

    Article  Google Scholar 

  • Chibazakura, T., Kawamura, F., Takahashi, H., 1991. Differential regulation of spo0A transcription in Bacillus subtilis: glucose epresses promoter switching at the initiation of sporulation. J. Bacteriol. 173, 2625–2632.

    Google Scholar 

  • Chibazakura, T., Kawamura, F., Asai, K., Takahashi, H., 1995. Effects of spo0 mutations on spo0A promoter switching at the initiation of sporulation in Bacillus subtilis. J. Bacteriol. 177, 4520–4523.

    Google Scholar 

  • Dartois, V., Djavakhishvili, T., Hoch, J.A., 1996. Identification of a membrane protein involved in activation of the KinB pathway to sporulation in Bacillus subtilis. J. Bacteriol. 178, 1178–1186.

    Google Scholar 

  • De Jong, H., Geiselmann, J., Batt, G., Hernandez, C., Page, M., 2004. Qualitative simulation of the initiation of sporulation in Bacillus subtilis. Bull. Math. Biol. 66, 261–299.

    Article  MathSciNet  Google Scholar 

  • Dunny, G.M., Leonard, B.A.B., 1997. Cell-cell communication in Gram-positive bacteria. Annu. Rev. Microbiol. 51, 527–564.

    Article  Google Scholar 

  • Eichenberger, P., Fujita, M., Jensen, S.T., Conlon, E.M., Rudner, D.Z., Wang, S.T., Ferguson, C., Haga, K., Sato, T., Liu, J.S., Losick, R., 2004. The program of gene transcription for a single differentiating cell type during sporulation in Bacillus subtilis. PLoS Biol. 2, 1664–1683.

    Article  Google Scholar 

  • Fujita, M., 2000. Temporal and selective association of multiple sigma factors with RNA polymerase during sporulation in Bacillus subtilis. Genes Cells 5, 79–88.

    Article  Google Scholar 

  • Gaur, N.K., Oppenheim, J., Smith, I., 1991. The Bacillus subtilis sin gene, a regulator of alternate developmental processes, codes for a DNA-binding protein. J. Bacteriol. 173, 678–686.

    Google Scholar 

  • González-Pastor, J.E., 2007. Multicellularity and social behaviour in Bacillus subtilis. In: Graumann, P. (Ed.), Bacillus: Cellular and Molecular Biology, pp. 419–449. Caister Academic Press, Wymondham.

    Google Scholar 

  • Healy, J., Weir, J., Smith, I., Losick, R., 1991. Post-transcriptional control of a sporulation regulatory gene encoding transcription factor σ H in Bacillus subtilis. Mol. Microbiol. 5, 477–487.

    Article  Google Scholar 

  • Hoch, J.A., 1993. Regulation of the phosphorelay and the initiation of sporulation in Bacillus subtilis. Annu. Rev. Microbiol. 47, 441–465.

    Article  Google Scholar 

  • Ireton, K., Rudner, D.Z., Siranosian, K.J., Grossman, A.D., 1993. Integration of multiple developmental signals in Bacillus subtilis through the Spo0A transcription factor. Genes Dev. 7, 283–294.

    Article  Google Scholar 

  • Jeong, J.W., Snay, J., Ataai, M.M., 1990. A mathematical model for examining growth and sporulation processes of Bacillus subtilis. Biotechnol. Bioeng. 35, 160–184.

    Article  Google Scholar 

  • Jiang, M., Grau, R., Perego, M., 2000a. Differential processing of propeptide inhibitors of Rap phosphatases in Bacillus subtilis. J. Bacteriol. 182, 303–310.

    Article  Google Scholar 

  • Jiang, M., Shao, W., Perego, M., Hoch, J.A., 2000b. Multiple histidine kinases regulate entry into stationary phase and sporulation in Bacillus subtilis. Mol. Microbiol. 38, 535–542.

    Article  Google Scholar 

  • Jones, D.T., Woods, D.R., 1986. Acetone-butanol fermentation revisited. Microbiol. Rev. 50, 484–524.

    Google Scholar 

  • Kallio, P.T., Fagelson, J.E., Hoch, J.A., Strauch, M.A., 1991. The transition state regulator Hpr of Bacillus subtilis is a DNA-binding protein. J. Biol. Chem. 266, 13411–13417.

    Google Scholar 

  • Ladds, J.C., Muchová, K., Blaškovič, D., Lewis, R.J., Brannigan, J.A., Wilkinson, A.J., Barák, I., 2003. The response regulator Spo0A from Bacillus subtilis is efficiently phosphorylated in Escherichia coli. FEMS Microbiol. Lett. 223, 153–157.

    Article  Google Scholar 

  • Lazazzera, B.A., Palmer, T., Quisel, J., Grossman, A.D., 1999. Cell density control of gene expression and development in Bacillus subtilis. In: Dunny, G.M., Winans, S.C. (Eds.), Cell-Cell Signaling in Bacteria, pp. 27–46. Am. Soc. Microbiol., Washington.

    Google Scholar 

  • Levdikov, V.M., Blagova, E., Joseph, P., Sonenshein, A.L., Wilkinson, A.J., 2006. The structure of CodY, a GTP- and isoleucine-responsive regulator of stationary phase and virulence in Gram-positive bacteria. J. Biol. Chem. 281, 11366–11373.

    Article  Google Scholar 

  • Lewandoski, M., Dubnau, E., Smith, I., 1986. Transcriptional regulation of the spo0F gene of Bacillus subtilis. J. Bacteriol. 168, 870–877.

    Google Scholar 

  • Lewis, R.J., Brannigan, J.A., Smith, I., Wilkinson, A.J., 1996. Crystallisation of the Bacillus subtilis sporulation inhibitor SinR, complexed with its antagonist, SinI. FEBS Lett. 378, 98–100.

    Article  Google Scholar 

  • Lewis, R.J., Scott, D.J., Brannigan, J.A., Ladds, J.C., Cervin, M.A., Spiegelman, G.B., Hoggett, J.G., Barák, I., Wilkinson, A.J., 2002. Dimer formation and transcription activation in the sporulation response regulator Spo0A. J. Mol. Biol. 316, 235–245.

    Article  Google Scholar 

  • Mandic-Mulec, I., Doukhan, L., Smith, I., 1995. The Bacillus subtilis SinR protein is a repressor of the key sporulation gene spo0A. J. Bacteriol. 177, 4619–4627.

    Google Scholar 

  • Millat, T., Bullinger, E., Rohwer, J., Wolkenhauer, O., 2007. Approximations and their consequences for dynamic modelling of signal transduction pathways. Math. Biosci. 207, 40–57.

    Article  MATH  MathSciNet  Google Scholar 

  • Molle, V., Fujita, M., Jensen, S.T., Eichenberger, P., González-Pastor, E., Liu, J.S., Losick, R., 2003a. The Spo0A regulon of Bacillus subtilis. Mol. Microbiol. 50, 1683–1701.

    Article  Google Scholar 

  • Molle, V., Nakaura, Y., Shivers, R.P., Yamaguchi, H., Losick, R., Fujita, Y., Sonenshein, A.L., 2003b. Additional targets of the Bacillus subtilis global regulator CodY identified by chromatin immunoprecipitation and genome-wide transcript anlaysis. J. Bacteriol. 185, 1911–1922.

    Article  Google Scholar 

  • Mueller, J.P., Bukusoglu, G., Sonenshein, A.L., 1992. Transcriptional regulation of Bacillus subtilis glucose starvation-inducible genes: control of gsiA by the ComA-ComP signal transduction system. J. Bacteriol. 174, 4361–4373.

    Google Scholar 

  • Ohlsen, K.L., Grimsley, J.K., Hoch, J.A., 1994. Deactivation of the sporulation transcription factor Spo0A by the Spo0E protein phosphatase. Proc. Natl. Acad. Sci. USA 91, 1756–1760.

    Article  Google Scholar 

  • Paredes, C.J., Alsaker, K.V., Papoutsakis, E.T., 2005. A comparative genomic view of clostridial sporulation and physiology. Nat. Rev. Microbiol. 3, 969–978.

    Article  Google Scholar 

  • Perego, M., 1997. A peptide export-import control circuit modulating bacterial development regulates protein phosphatases of the phosphorelay. Proc. Natl. Acad. Sci. USA 94, 8612–8617.

    Article  Google Scholar 

  • Perego, M., 1999. Self-signalling by phr peptides modulates Bacillus subtilis development. In: Dunny, G.M., Winans, S.C. (Eds.), Cell-Cell Signaling in Bacteria, pp. 243–258. Am. Soc. Microbiol., Washington.

    Google Scholar 

  • Perego, M., Brannigan, J.A., 2001. Pentapeptide regulation of aspartyl-phosphate phosphatases. Peptides 22, 1541–1547.

    Article  Google Scholar 

  • Perego, M., Hoch, J.A., 1987. Isolation and sequence of the spo0E gene: its role in initiation of sporulation in Bacillus subtilis. Mol. Microbiol. 1, 125–132.

    Article  Google Scholar 

  • Perego, M., Hoch, J.A., 1991. Negative regulation of Bacillus subtilis sporulation by the spo0E gene product. J. Bacteriol. 173, 2514–2520.

    Google Scholar 

  • Perego, M., Hoch, J.A., 1996. Cell-cell communication regulates the effects of protein aspartate phosphatases on the phosphorelay controlling development in Bacillus subtilis. Proc. Natl. Acad. Sci. USA 93, 1549–1553.

    Article  Google Scholar 

  • Perego, M., Hanstein, C., Welsh, K.M., Djavakhishvili, T., Glaser, P., Hoch, J.A., 1994. Multiple proteinaspartate phosphatases provide a mechanism for the integration of diverse signals in the control of development in Bacillus subtilis. Cell 79, 1047–1055.

    Article  Google Scholar 

  • Piggot, P.J., Coote, J.G., 1976. Genetic aspects of bacterial endospore formation. Bacteriol. Rev. 40, 908–962.

    Google Scholar 

  • Piggot, P.J., Hilbert, D.W., 2004. Sporulation of Bacillus subtilis. Curr. Opin. Microbiol. 7, 579–586.

    Article  Google Scholar 

  • Predich, M., Nair, G., Smith, I., 1992. Bacillus subtilis early sporulation genes kinA, spo0F, and spo0A are transcribed by the RNA polymerase containing σ H. J. Bacteriol. 174, 2771–2778.

    Google Scholar 

  • Ratnayake-Lecamwasam, M., Serror, P., Wong, K., Sonenshein, A.L., 2001. Bacillus subtilis CodY represses early-stationary-phase genes by sensing GTP levels. Genes Dev. 15, 1093–1103.

    Article  Google Scholar 

  • Rowland, S.L., Burkholder, W.F., Cunningham, K.A., Maciejewski, M.W., Grossman, A.D., King, G.F., 2004. Structure and mechanism of action of Sda, an inhibitor of the histidine kinases that regulate initiation of sporulation in Bacillus subtilis. Mol. Cell 13, 689–701.

    Article  Google Scholar 

  • Scott, D.J., Leejeerajumnean, S., Brannigan, J.A., Lewis, R.J., Wilkinson, A.J., Hoggett, J.G., 1999. Quaternary re-arrangement analysed by spectral enhancement: the interaction of a sporulation repressor with its antagonist. J. Mol. Biol. 293, 997–1004.

    Article  Google Scholar 

  • Shafikhani, S.H., Mandi-Mulec, I., Strauch, M.A., Smith, I., Leighton, T., 2002. Postexponential regulation of sin operon expression in Bacillus subtilis. J. Bacteriol. 184, 564–571.

    Article  Google Scholar 

  • Smits, W.K., Bongiorni, C., Veening, J., Hamoen, L.W., Kuipers, O.P., Perego, M., 2007. Temporal separation of distinct differentiation pathways by a dual specificity Rap-Phr system in Bacillus subtilis. Mol. Microbiol. 65, 103–120.

    Article  Google Scholar 

  • Sonenshein, A.L., 2000. Control of sporulation initiation in Bacillus subtilis. Curr. Opin. Microbiol. 3, 561–566.

    Article  Google Scholar 

  • Stephenson, S.J., Perego, M., 2002. Interaction surface of the Spo0A response regulator with the Spo0E phosphatase. Mol. Microbiol. 44, 1455–1467.

    Article  Google Scholar 

  • Strauch, M.A., 1995. Delineation of AbrB-binding sites on the Bacillus subtilis spo0H, kinB, ftsAZ, and pbpE promoters and use of a derived homology to identify a previously unsuspected binding site in the bsuB1 methylase promoter. J. Bacteriol. 177, 6999–7002.

    Google Scholar 

  • Strauch, M.A., Hoch, J.A., 1993. Transition-state regulators: sentinels of Bacillus subtilis postexponential gene expression. Mol. Microbiol. 7, 337–342.

    Article  Google Scholar 

  • Strauch, M.A., Perego, M., Burbulys, D., Hoch, J.A., 1989. The transition state transcription regulator AbrB of Bacillus subtilis is autoregulated during vegetative growth. Mol. Microbiol. 3, 1203–1209.

    Article  Google Scholar 

  • Strauch, M., Webb, V., Spiegelman, G., Hoch, J.A., 1990. The Spo0A protein of Bacillus subtilis is a repressor of the abrB gene. Proc. Natl. Acad. Sci. USA 87, 1801–1805.

    Article  Google Scholar 

  • Strauch, M.A., Trach, K.A., Day, J., Hoch, J.A., 1992. Spo0A activates and represses its own synthesis by binding at its dual promoters. Biochimie 74, 619–626.

    Article  Google Scholar 

  • Strauch, M.A., Wu, J., Jonas, R.H., Hoch, J.A., 1993. A positive feedback loop controls transcription of the spo0F gene, a component of the sporulation phosphorelay in Bacillus subtilis. Mol. Microbiol. 7, 967–974.

    Article  Google Scholar 

  • Süel, G.M., Garcia-Ojalvo, J., Liberman, L.M., Elowitz, M.B., 2006. An excitable gene regulatory circuit induces transient cellular differentiation. Nature 440, 545–550.

    Article  Google Scholar 

  • Süel, G.M., Kulkarni, R.P., Dworkin, J., Garcia-Ojalvo, J., Elowitz, M.B., 2007. Tunability and noise dependence in differentiation dynamics. Science 315, 1716–1719.

    Article  Google Scholar 

  • Trach, K.A., Hoch, J.A., 1993. Multisensory activation of the phosphorelay initiating sporulation in Bacillus subtilis: identification and sequence of the protein kinase of the alternate pathway. Mol. Microbiol. 8, 69–79.

    Article  Google Scholar 

  • Varughese, K.I., Madhusudan, Zhou X.Z., Whiteley, J.M., Hoch, J.A., 1998. Formation of a novel fourhelix bundle and molecular recognition sites by dimerization of a response regulator phosphotransferase. Mol. Cell 2, 485–493.

    Article  Google Scholar 

  • Vaughn, J.L., Feher, V., Naylor, S., Strauch, M.A., Cavanagh, J., 2000. Novel DNA binding domain and genetic regulation model of Bacillus subtilis transition state regulator AbrB. Nat. Struct. Biol. 7, 1139–1146.

    Article  Google Scholar 

  • Vilar, J.M.G., Kueh, H.Y., Barkai, N., Leibler, S., 2002. Mechanisms of noise-resistance in genetic oscillators. Proc. Natl. Acad. Sci. USA 99, 5988–5992.

    Article  Google Scholar 

  • Voigt, C.A., Wolf, D.M., Arkin, A.P., 2005. The Bacillus subtilis sin operon: an evolvable network motif. Genetics 169, 1187–1202.

    Article  Google Scholar 

  • Wang, L., Fabret, C., Kanamaru, K., Stephenson, K., Dartois, V., Perego, M., Hoch, J.A., 2001. Dissection of the functional and structural domains of phosphorelay histidine kinase A of Bacillus subtilis. J. Bacteriol. 183, 2795–2802.

    Article  Google Scholar 

  • Weir, J., Predich, M., Dubnau, E., Mair, G., Smith, I., 1991. Regulation of spo0H, a gene coding for the Bacillus subtilis σ H factor. J. Bacteriol. 173, 521–529.

    Google Scholar 

  • Wilson, M., McNab, R., Henderson, B., 2002. Bacterial Disease Mechanisms, an Introduction to Cellular Microbiology. Cambridge University Press, Cambridge.

    Google Scholar 

  • Xu, K., Strauch, M.A., 1996. In vitro selection of optimal AbrB-binding sites: comparison to known in vivo sites indicates exibility in AbrB binding and recognition of three-dimensional DNA structures. Mol. Microbiol. 19, 145–158.

    Article  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Centre for Mathematical Medicine and Biology, School of Mathematical Sciences, University of Nottingham, Nottingham, NG7 2RD, UK

    Sara Jabbari & John R. King

  2. Centre for Biomolecular Sciences, University of Nottingham, Nottingham, NG7 2RD, UK

    John T. Heap

Authors
  1. Sara Jabbari
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. John T. Heap
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. John R. King
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Sara Jabbari.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Jabbari, S., Heap, J.T. & King, J.R. Mathematical Modelling of the Sporulation-Initiation Network in Bacillus Subtilis Revealing the Dual Role of the Putative Quorum-Sensing Signal Molecule PhrA. Bull. Math. Biol. 73, 181–211 (2011). https://doi.org/10.1007/s11538-010-9530-7

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s11538-010-9530-7

Keywords

Search

Navigation