Skip to main content
SpringerLink
Log in

Mathematical model of flagella gene expression dynamics in Salmonella enterica serovar typhimurium

  • Research Article
  • Published:
Systems and Synthetic Biology

Abstract

Flagellar assembly in Salmonella is controlled by an intricate genetic and biochemical network. This network comprises of a number of inter-connected feedback loops, which control the assembly process dynamically. Critical among these are the FliA–FlgM feedback, FliZ-mediated positive feedback, and FliT-mediated negative feedback. In this work, we develop a mathematical model to track the dynamics of flagellar gene expression in Salmonella. Analysis of our model demonstrates that the network is wired to not only control the transition of the cell from a non-flagellated to a flagellated state, but to also control dynamics of gene expression during cell division. Further, we predict that FliZ encoded in the flagellar regulon acts as a critical secretion-dependent molecular link between flagella and Salmonella Pathogenicity Island 1 gene expression. Sensitivity analysis of the model demonstrates that the flagellar regulatory network architecture is extremely robust to mutations.

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

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5
Fig. 6
Fig. 7
Fig. 8
Fig. 9

Similar content being viewed by others

References

  • Aizawa SI, Kubori T (1998) Bacterial flagellation and cell division. Genes Cells 3:625–634

    Article  CAS  PubMed  Google Scholar 

  • Aldridge P, Karlinsey J, Hughes KT (2003) The type III secretion chaperone FlgN regulates flagellar assembly via a negative feedback loop containing its chaperone substrates FlgK and FlgL. Mol Microbiol 49:1333–1345

    Article  CAS  PubMed  Google Scholar 

  • Aldridge PD, Karlinsey JE, Aldridge C, Birchall C, Thompson D, Yagasaki J, Hughes KT (2006) The flagellar-specific transcription factor, sigma28, is the type III secretion chaperone for the flagellar-specific anti-sigma28 factor FlgM. Genes Dev 20:2315–2326

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  • Aldridge C, Poonchareon K, Saini S, Ewen T, Soloyva A, Rao CV, Imada K, Minamino T, Aldridge PD (2010) The interaction dynamics of a negative feedback loop regulates flagellar number in Salmonella enterica serovar typhimurium. Mol Microbiol 78:1416–1430. doi:10.1111/j.1365-2958.2010.07415.x

    Article  CAS  PubMed  Google Scholar 

  • Auvray F, Thomas J, Fraser GM, Hughes C (2001) Flagellin polymerisation control by a cytosolic export chaperone. J Mol Biol 308:221–229

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  • Barembruch C, Hengge R (2007) Cellular levels and activity of the flagellar sigma factor FliA of Escherichia coli are controlled by FlgM-modulated proteolysis. Mol Microbiol 65:76–89 Epub 2007 May 2030

    Article  CAS  PubMed  Google Scholar 

  • Berg HC (2003) The rotary motor of bacterial flagella. Annu Rev Biochem 72:19–54 Epub 2002 Dec 2011

    Article  CAS  PubMed  Google Scholar 

  • Brandman O, Ferrell JE Jr, Li R, Meyer T (2005) Interlinked fast and slow positive feedback loops drive reliable cell decisions. Science 310:496–498

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  • Burton RF (2000) Physiology by numbers: an encouragement to quantitative thinking, 2nd edn. Cambridge University Press, Cambridge

    Book  Google Scholar 

  • Chadsey MS, Hughes KT (2001) A multipartite interaction between Salmonella transcription factor sigma28 and its anti-sigma factor FlgM: implications for sigma28 holoenzyme destabilization through stepwise binding. J Mol Biol 306:915–929

    Article  CAS  PubMed  Google Scholar 

  • Chadsey MS, Karlinsey JE, Hughes KT (1998) The flagellar anti-sigma factor FlgM actively dissociates Salmonella typhimurium sigma28 RNA polymerase holoenzyme. Genes Dev 12:3123–3136

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  • Chevance FF, Hughes KT (2008) Coordinating assembly of a bacterial macromolecular machine. Nat Rev Microbiol 6:455–465

    Article  CAS  PubMed  Google Scholar 

  • Chilcott GS, Hughes KT (2000) Coupling of flagellar gene expression to flagellar assembly in Salmonella enterica serovar typhimurium and Escherichia coli. Microbiol Mol Biol Rev 64:694–708

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  • Chubiz JE, Golubeva YA, Lin D, Miller LD, Slauch JM (2010) FliZ regulates expression of the Salmonella pathogenicity island 1 invasion locus by controlling HilD protein activity in Salmonella enterica serovar typhimurium. J Bacteriol 192:6261–6270. doi:10.1128/JB.00635-00610

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  • Clarke MB, Sperandio V (2005) Transcriptional regulation of flhDC by QseBC and sigma (FliA) in enterohaemorrhagic Escherichia coli. Mol Microbiol 57:1734–1749

    Article  CAS  PubMed  Google Scholar 

  • Clegg S, Hughes KT (2002) FimZ is a molecular link between sticking and swimming in Salmonella enterica serovar typhimurium. J Bacteriol 184:1209–1213

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  • Ellermeier CD, Slauch JM (2003) RtsA and RtsB coordinately regulate expression of the invasion and flagellar genes in Salmonella enterica serovar typhimurium. J Bacteriol 185:5096–5108

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  • Freeman M (2000) Feedback control of intercellular signalling in development. Nature 408:313–319

    Article  CAS  PubMed  Google Scholar 

  • Galeva A, Moroz N, Yoon YH, Hughes KT, Samatey FA, Kostyukova AS (2014) Bacterial flagellin-specific chaperone FliS interacts with anti-sigma factor FlgM. J Bacteriol 196:1215–1221. doi:10.1128/JB.01278-01213

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  • Hughes KT, Gillen KL, Semon MJ, Karlinsey JE (1993) Sensing structural intermediates in bacterial flagellar assembly by export of a negative regulator. Science 262:1277–1280

    Article  CAS  PubMed  Google Scholar 

  • Ikebe T, Iyoda S, Kutsukake K (1999a) Promoter analysis of the class 2 flagellar operons of Salmonella. Genes Genet Syst 74:179–183

    Article  CAS  PubMed  Google Scholar 

  • Ikebe T, Iyoda S, Kutsukake K (1999b) Structure and expression of the fliA operon of Salmonella typhimurium. Microbiology 145:1389–1396

    Article  CAS  PubMed  Google Scholar 

  • Iyoda S, Kamidoi T, Hirose K, Kutsukake K, Watanabe H (2001) A flagellar gene fliZ regulates the expression of invasion genes and virulence phenotype in Salmonella enterica serovar typhimurium. Microb Pathog 30:81–90

    Article  CAS  PubMed  Google Scholar 

  • Jones CJ, Aizawa S (1991) The bacterial flagellum and flagellar motor: structure, assembly and function. Adv Microb Physiol 32:109–172

    Article  CAS  PubMed  Google Scholar 

  • Kage H, Takaya A, Ohya M, Yamamoto T (2008) Coordinated regulation of expression of Salmonella pathogenicity island 1 and flagellar type III secretion systems by ATP-dependent ClpXP protease. J Bacteriol 190:2470–2478. doi:10.1128/JB.01385-01307

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  • Kalir S, Mangan S, Alon U (2005) A coherent feed-forward loop with a SUM input function prolongs flagella expression in Escherichia coli. Mol Syst Biol 1(2005):0006 Epub 2005 Mar 2029

    PubMed  Google Scholar 

  • Karlinsey JE, Lonner J, Brown KL, Hughes KT (2000a) Translation/secretion coupling by type III secretion systems. Cell 102:487–497

    Article  CAS  PubMed  Google Scholar 

  • Karlinsey JE, Tanaka S, Bettenworth V, Yamaguchi S, Boos W, Aizawa SI, Hughes KT (2000b) Completion of the hook-basal body complex of the Salmonella typhimurium flagellum is coupled to FlgM secretion and fliC transcription. Mol Microbiol 37:1220–1231

    Article  CAS  PubMed  Google Scholar 

  • Kawagishi I, Muller V, Williams AW, Irikura VM, Macnab RM (1992) Subdivision of flagellar region III of the Escherichia coli and Salmonella typhimurium chromosomes and identification of two additional flagellar genes. J Gen Microbiol 138:1051–1065

    Article  CAS  PubMed  Google Scholar 

  • Kim D, Kwon YK, Cho KH (2007) Coupled positive and negative feedback circuits form an essential building block of cellular signaling pathways. BioEssays 29:85–90

    Article  CAS  PubMed  Google Scholar 

  • Ko M, Park C (2000) Two novel flagellar components and H-NS are involved in the motor function of Escherichia coli. J Mol Biol 303:371–382

    Article  CAS  PubMed  Google Scholar 

  • Koirala S, Mears P, Sim M, Golding I, Chemla YR, Aldridge PD, Rao CV (2014) A nutrient-tunable bistable switch controls motility in Salmonella enterica serovar typhimurium. mBio 5:e01611–e01614

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  • Kutsukake K (1997) Autogenous and global control of the flagellar master operon, flhD, in Salmonella typhimurium. Mol Gen Genet 254:440–448

    Article  CAS  PubMed  Google Scholar 

  • Kutsukake K, Ide N (1995) Transcriptional analysis of the flgK and fliD operons of Salmonella typhimurium which encode flagellar hook-associated proteins. Mol Gen Genet 247:275–281

    Article  CAS  PubMed  Google Scholar 

  • Kutsukake K, Iino T (1994) Role of the FliA-FlgM regulatory system on the transcriptional control of the flagellar regulon and flagellar formation in Salmonella typhimurium. J Bacteriol 176:3598–3605

    PubMed Central  CAS  PubMed  Google Scholar 

  • Kutsukake K, Ikebe T, Yamamoto S (1999) Two novel regulatory genes, fliT and fliZ, in the flagellar regulon of Salmonella. Genes Genet Syst 74:287–292

    Article  CAS  PubMed  Google Scholar 

  • Lostroh CP, Lee CA (2001) The Salmonella pathogenicity island-1 type III secretion system. Microbes Infect 3:1281–1291

    Article  CAS  PubMed  Google Scholar 

  • Lucas RL, Lostroh CP, DiRusso CC, Spector MP, Wanner BL, Lee CA (2000) Multiple factors independently regulate hilA and invasion gene expression in Salmonella enterica serovar typhimurium. J Bacteriol 182:1872–1882

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  • Macnab RM (1977) Bacterial flagella rotating in bundles: a study in helical geometry. Proc Natl Acad Sci USA 74:221–225

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  • Macnab RM (1999) The bacterial flagellum: reversible rotary propellor and type III export apparatus. J Bacteriol 181:7149–7153

    PubMed Central  CAS  PubMed  Google Scholar 

  • Macnab RM (2003) How bacteria assemble flagella. Annu Rev Microbiol 57:77–100 Epub 2003 May 2001

    Article  CAS  PubMed  Google Scholar 

  • Mariconda S, Wang Q, Harshey RM (2006) A mechanical role for the chemotaxis system in swarming motility. Mol Microbiol 60:1590–1602

    Article  CAS  PubMed  Google Scholar 

  • Mitrophanov AY, Groisman EA (2008) Positive feedback in cellular control systems. BioEssays 30:542–555. doi:10.1002/bies.20769

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  • Muskotal A, Kiraly R, Sebestyen A, Gugolya Z, Vegh BM, Vonderviszt F (2006) Interaction of FliS flagellar chaperone with flagellin. FEBS Lett 580:3916–3920 Epub 2006 Jun 3921

    Article  CAS  PubMed  Google Scholar 

  • Mytelka DS, Chamberlin MJ (1996) Escherichia coli fliAZY operon. J Bacteriol 178:24–34

    PubMed Central  CAS  PubMed  Google Scholar 

  • Ohnishi K, Kutsukake K, Suzuki H, Lino T (1992) A novel transcriptional regulation mechanism in the flagellar regulon of Salmonella typhimurium: an antisigma factor inhibits the activity of the flagellum-specific sigma factor, sigma F. Mol Microbiol 6:3149–3157

    Article  CAS  PubMed  Google Scholar 

  • Paulsson J (2005) Models of stochastic gene expression. Physics of Life Reviews 2:157–175

    Article  Google Scholar 

  • Rosu V, Hughes KT (2006) sigma28-dependent transcription in Salmonella enterica is independent of flagellar shearing. J Bacteriol 188:5196–5203

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  • Saini S, Rao CV (2010) SprB is the molecular link between Salmonella pathogenicity island 1 (SPI1) and SPI4. J Bacteriol 192:2459–2462. doi:10.1128/JB.00047-00010

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  • Saini S, Brown JD, Aldridge PD, Rao CV (2008) FliZ is a posttranslational activator of FlhD4C2-dependent flagellar gene expression. J Bacteriol 190:4979–4988. doi:10.1128/JB.01996-01907

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  • Saini S, Koirala S, Floess E, Mears PJ, Chemla YR, Golding I, Aldridge C, Aldridge PD, Rao CV (2010a) FliZ induces a kinetic switch in flagellar gene expression. J Bacteriol 192:6477–6481

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  • Saini S, Slauch JM, Aldridge PD, Rao CV (2010b) Role of cross talk in regulating the dynamic expression of the flagellar Salmonella pathogenicity island 1 and type 1 fimbrial genes. J Bacteriol 192:5767–5777. doi:10.1128/JB.00624-00610

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  • Saini S, Floess E, Aldridge C, Brown J, Aldridge PD, Rao CV (2011) Continuous control of flagellar gene expression by the sigma28-FlgM regulatory circuit in Salmonella enterica. Mol Microbiol 79:264–278. doi:10.1111/j.1365-2958.2010.07444.x

    Article  CAS  PubMed  Google Scholar 

  • Shin D, Lee EJ, Huang H, Groisman EA (2006) A positive feedback loop promotes transcription surge that jump-starts Salmonella virulence circuit. Science 314:1607–1609

    Article  CAS  PubMed  Google Scholar 

  • Silverman M, Simon M (1974) Flagellar rotation and the mechanism of bacterial motility. Nature 249:73–74

    Article  CAS  PubMed  Google Scholar 

  • Takaya A, Erhardt M, Karata K, Winterberg K, Yamamoto T, Hughes KT (2012) YdiV: a dual function protein that targets FlhDC for ClpXP-dependent degradation by promoting release of DNA-bound FlhDC complex. Mol Microbiol 83:1268–1284. doi:10.1111/j.1365-2958.2012.08007.x

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  • Tanabe Y, Wada T, Ono K, Abo T, Kutsukake K (2011) The transcript from the sigma(28)-dependent promoter is translationally inert in the expression of the sigma(28)-encoding gene fliA in the fliAZ operon of Salmonella enterica serovar typhimurium. J Bacteriol 193:6132–6141. doi:10.1128/JB.05909-05911

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  • Teplitski M, Goodier RI, Ahmer BM (2003) Pathways leading from BarA/SirA to motility and virulence gene expression in Salmonella. J Bacteriol 185:7257–7265

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  • Thomas R, Thieffry D, Kaufman M (1995) Dynamical behaviour of biological regulatory networks–I. Biological role of feedback loops and practical use of the concept of the loop-characteristic state. Bull Math Biol 57:247–276

    Article  CAS  PubMed  Google Scholar 

  • Tomoyasu T, Ohkishi T, Ukyo Y, Tokumitsu A, Takaya A, Suzuki M, Sekiya K, Matsui H, Kutsukake K, Yamamoto T (2002) The ClpXP ATP-dependent protease regulates flagellum synthesis in Salmonella enterica serovar typhimurium. J Bacteriol 184:645–653

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  • Wada T, Tanabe Y, Kutsukake K (2011) FliZ acts as a repressor of the ydiV gene, which encodes an anti-FlhD4C2 factor of the flagellar regulon in Salmonella enterica serovar typhimurium. J Bacteriol 193:5191–5198. doi:10.1128/JB.05441-05411

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  • Wang S, Fleming RT, Westbrook EM, Matsumura P, McKay DB (2006) Structure of the Escherichia coli FlhDC complex, a prokaryotic heteromeric regulator of transcription. J Mol Biol 355:798–808 Epub 2005 Nov 2022

    Article  CAS  PubMed  Google Scholar 

  • Wei BL, Brun-Zinkernagel AM, Simecka JW, Pruss BM, Babitzke P, Romeo T (2001) Positive regulation of motility and flhDC expression by the RNA-binding protein CsrA of Escherichia coli. Mol Microbiol 40:245–256

    Article  CAS  PubMed  Google Scholar 

  • Wu KH, Wang KC, Lee LW, Huang YN, Yeh KS (2012) A constitutively mannose-sensitive agglutinating Salmonella enterica subsp enterica serovar typhimurium strain, carrying a transposon in the fimbrial usher gene stbC, exhibits multidrug resistance and flagellated phenotypes. ScientificWorldJournal 2012:280264. doi:10.1100/2012/280264 Epub 282012 Mar 280261

    PubMed Central  PubMed  Google Scholar 

  • Yamamoto S, Kutsukake K (2006) FliT acts as an anti-FlhD2C2 factor in the transcriptional control of the flagellar regulon in Salmonella enterica serovar typhimurium. J Bacteriol 188:6703–6708

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  • Yanagihara S, Iyoda S, Ohnishi K, Iino T, Kutsukake K (1999) Structure and transcriptional control of the flagellar master operon of Salmonella typhimurium. Genes Genet Syst 74:105–111

    Article  CAS  PubMed  Google Scholar 

  • Yokoseki T, Kutsukake K, Ohnishi K, Iino T (1995) Functional analysis of the flagellar genes in the fliD operon of Salmonella typhimurium. Microbiology 141:1715–1722

    Article  CAS  PubMed  Google Scholar 

  • Yonekura K, Maki-Yonekura S, Namba K (2003) Complete atomic model of the bacterial flagellar filament by electron cryomicroscopy. Nature 424:643–650

    Article  CAS  PubMed  Google Scholar 

Download references

Acknowledgments

This work was funded by the Innovative Young Biotechnologist Award (IYBA) 2010 program of the Department of Biotechnology, Ministry of Science and Technology, Government of India.

Author information

Author notes

    Authors and Affiliations

    1. Department of Chemical Engineering, Indian Institute of Technology Bombay, Powai, Mumbai, 400076, Maharashtra, India

      Kirti Jain, Amit Pradhan, Chaitanya Mokashi & Supreet Saini

    Authors
    1. Kirti Jain
      View author publications

      You can also search for this author in PubMed Google Scholar

    2. Amit Pradhan
      View author publications

      You can also search for this author in PubMed Google Scholar

    3. Chaitanya Mokashi
      View author publications

      You can also search for this author in PubMed Google Scholar

    4. Supreet Saini
      View author publications

      You can also search for this author in PubMed Google Scholar

    Corresponding author

    Correspondence to Supreet Saini.

    Additional information

    Kirti Jain and Amit Pradhan have contributed equally to this study.

    Electronic supplementary material

    Below is the link to the electronic supplementary material.

    Supplementary material 1 (DOCX 105 kb)

    Rights and permissions

    Reprints and permissions

    About this article

    Check for updates. Verify currency and authenticity via CrossMark

    Cite this article

    Jain, K., Pradhan, A., Mokashi, C. et al. Mathematical model of flagella gene expression dynamics in Salmonella enterica serovar typhimurium . Syst Synth Biol 9, 19–31 (2015). https://doi.org/10.1007/s11693-015-9160-3

    Download citation

    • Received:

    • Revised:

    • Accepted:

    • Published:

    • Issue Date:

    • DOI: https://doi.org/10.1007/s11693-015-9160-3

    Keywords

    Search

    Navigation