Protein-protein interaction network controlling establishment and maintenance of switchable cell polarity

Autoři: Luís António Menezes Carreira aff001;  Filipe Tostevin aff001;  Ulrich Gerland aff002;  Lotte Søgaard-Andersen aff001
Působiště autorů: Department of Ecophysiology, Max Planck Institute for Terrestrial Microbiology, Marburg, Germany aff001;  Physik-Department, Technische Universität München, James Franck Straße, Garching, Germany aff002
Vyšlo v časopise: Protein-protein interaction network controlling establishment and maintenance of switchable cell polarity. PLoS Genet 16(6): e32767. doi:10.1371/journal.pgen.1008877
Kategorie: Research Article
doi: 10.1371/journal.pgen.1008877


Cell polarity underlies key processes in all cells, including growth, differentiation and division. In the bacterium Myxococcus xanthus, front-rear polarity is crucial for motility. Notably, this polarity can be inverted, independent of the cell-cycle, by chemotactic signaling. However, a precise understanding of the protein network that establishes polarity and allows for its inversion has remained elusive. Here, we use a combination of quantitative experiments and data-driven theory to unravel the complex interplay between the three key components of the M. xanthus polarity module. By studying each of these components in isolation and their effects as we systematically reconstruct the system, we deduce the network of effective interactions between the polarity proteins. RomR lies at the root of this network, promoting polar localization of the other components, while polarity arises from interconnected negative and positive feedbacks mediated by the small GTPase MglA and its cognate GAP MglB, respectively. We rationalize this network topology as operating as a spatial toggle switch, providing stable polarity for persistent cell movement whilst remaining responsive to chemotactic signaling and thus capable of polarity inversions. Our results have implications not only for the understanding of polarity and motility in M. xanthus but also, more broadly, for dynamic cell polarity.

Klíčová slova:

Cell cycle and cell division – Cell polarity – Fluorescence imaging – Fluorescence microscopy – Guanine nucleotide exchange factors – Guanosine triphosphatase – Mathematical models – Protein interaction networks


1. Rafelski SM, Marshall WF. Building the cell: design principles of cellular architecture. Nat Rev Mol Cell Biol. 2008;9:593. doi: 10.1038/nrm2460 18648373

2. Treuner-Lange A, Søgaard-Andersen L. Regulation of cell polarity in bacteria. J Cell Biol. 2014;206:7–17. doi: 10.1083/jcb.201403136 25002676

3. Laloux G, Jacobs-Wagner C. How do bacteria localize proteins to the cell pole? J Cell Sci. 2014;127:11–9. doi: 10.1242/jcs.138628 24345373

4. St Johnston D, Ahringer J. Cell Polarity in Eggs and Epithelia: Parallels and Diversity. Cell. 2010;141:757–74. doi: 10.1016/j.cell.2010.05.011 20510924

5. Ridley AJ, Schwartz MA, Burridge K, Firtel RA, Ginsberg MH, Borisy G, et al. Cell migration: integrating signals from front to back. Science. 2003;302:1704–9. doi: 10.1126/science.1092053 14657486

6. Schumacher D, Søgaard-Andersen L. Regulation of Cell Polarity in Motility and Cell Division in Myxococcus xanthus. Annu Rev Microbiol. 2017;71:61–78. doi: 10.1146/annurev-micro-102215-095415 28525300

7. Chau AH, Walter JM, Gerardin J, Tang C, Lim WA. Designing synthetic regulatory networks capable of self-organizing cell polarization. Cell. 2012;151:320–32. doi: 10.1016/j.cell.2012.08.040 23039994

8. Zhang Y, Guzzo M, Ducret A, Li YZ, Mignot T. A dynamic response regulator protein modulates G-protein-dependent polarity in the bacterium Myxococcus xanthus. PLoS Genet. 2012;8:e1002872. doi: 10.1371/journal.pgen.1002872 22916026

9. Skerker JM, Berg HC. Direct observation of extension and retraction of type IV pili. Proc Natl Acad Sci USA. 2001;98:6901–4. doi: 10.1073/pnas.121171698 11381130

10. Faure LM, Fiche JB, Espinosa L, Ducret A, Anantharaman V, Luciano J, et al. The mechanism of force transmission at bacterial focal adhesion complexes. Nature. 2016;539:530–5. doi: 10.1038/nature20121 27749817

11. Treuner-Lange A, Macia E, Guzzo M, Hot E, Faure LM, Jakobczak B, et al. The small G-protein MglA connects to the MreB actin cytoskeleton at bacterial focal adhesions. J Cell Biol. 2015;210:243–56. doi: 10.1083/jcb.201412047 26169353

12. Jakobczak B, Keilberg D, Wuichet K, Søgaard-Andersen L. Contact- and Protein Transfer-Dependent Stimulation of Assembly of the Gliding Motility Machinery in Myxococcus xanthus. PLoS Genet. 2015;11:e1005341. doi: 10.1371/journal.pgen.1005341 26132848

13. Sun M, Wartel M, Cascales E, Shaevitz JW, Mignot T. Motor-driven intracellular transport powers bacterial gliding motility. Proc Natl Acad Sci USA. 2011;108:7559–64. doi: 10.1073/pnas.1101101108 21482768

14. Nan B, Chen J, Neu JC, Berry RM, Oster G, Zusman DR. Myxobacteria gliding motility requires cytoskeleton rotation powered by proton motive force. Proc Natl Acad Sci USA. 2011;108:2498–503. doi: 10.1073/pnas.1018556108 21248229

15. Luciano J, Agrebi R, Le Gall AV, Wartel M, Fiegna F, Ducret A, et al. Emergence and modular evolution of a novel motility machinery in bacteria. PLoS Genet. 2011;7:e1002268. doi: 10.1371/journal.pgen.1002268 21931562

16. Nan B, Mauriello EM, Sun IH, Wong A, Zusman DR. A multi-protein complex from Myxococcus xanthus required for bacterial gliding motility. Mol Microbiol. 2010;76:1539–54. doi: 10.1111/j.1365-2958.2010.07184.x 20487265

17. Mignot T, Shaevitz JW, Hartzell PL, Zusman DR. Evidence that focal adhesion complexes power bacterial gliding motility. Science. 2007;315:853–6. doi: 10.1126/science.1137223 17289998

18. Mignot T, Merlie JP Jr., Zusman DR. Regulated pole-to-pole oscillations of a bacterial gliding motility protein. Science. 2005;310:855–7. doi: 10.1126/science.1119052 16272122

19. Szadkowski D, Harms A, Carreira LAM, Wigbers M, Potapova A, Wuichet K, et al. Spatial control of the GTPase MglA by localized RomR-RomX GEF and MglB GAP activities enables Myxococcus xanthus motility. Nat Microbiol. 2019;4:1344–55. doi: 10.1038/s41564-019-0451-4 31110363

20. Keilberg D, Wuichet K, Drescher F, Søgaard-Andersen L. A response regulator interfaces between the Frz chemosensory system and the MglA/MglB GTPase/GAP module to regulate polarity in Myxococcus xanthus. PLoS Genet. 2012;8:e1002951. doi: 10.1371/journal.pgen.1002951 23028358

21. Zhang Y, Franco M, Ducret A, Mignot T. A bacterial Ras-like small GTP-binding protein and its cognate GAP establish a dynamic spatial polarity axis to control directed motility. PLoS Biol. 2010;8:e1000430. doi: 10.1371/journal.pbio.1000430 20652021

22. Leonardy S, Miertzschke M, Bulyha I, Sperling E, Wittinghofer A, Søgaard-Andersen L. Regulation of dynamic polarity switching in bacteria by a Ras-like G-protein and its cognate GAP. EMBO J. 2010;29:2276–89. doi: 10.1038/emboj.2010.114 20543819

23. Ridley AJ. Life at the leading edge. Cell. 2011;145:1012–22. doi: 10.1016/j.cell.2011.06.010 21703446

24. Wittinghofer A, Vetter IR. Structure-function relationships of the G domain, a canonical switch motif. Annu Rev Biochem. 2011;80:943–71. doi: 10.1146/annurev-biochem-062708-134043 21675921

25. Bos JL, Rehmann H, Wittinghofer A. GEFs and GAPs: critical elements in the control of small G proteins. Cell. 2007;129:865–77. doi: 10.1016/j.cell.2007.05.018 17540168

26. Mauriello EM, Mouhamar F, Nan B, Ducret A, Dai D, Zusman DR, et al. Bacterial motility complexes require the actin-like protein, MreB and the Ras homologue, MglA. EMBO J. 2010;29:315–26. doi: 10.1038/emboj.2009.356 19959988

27. Hodgkin J, Kaiser D. Genetics of gliding motility in Myxococcus xanthus (Myxobacterales): Two gene systems control movement. Mol Gen Genet. 1979;171:177–91.

28. Miertzschke M, Koerner C, Vetter IR, Keilberg D, Hot E, Leonardy S, et al. Structural analysis of the Ras-like G protein MglA and its cognate GAP MglB and implications for bacterial polarity. EMBO J. 2011;30:4185–97. doi: 10.1038/emboj.2011.291 21847100

29. Leonardy S, Freymark G, Hebener S, Ellehauge E, Søgaard-Andersen L. Coupling of protein localization and cell movements by a dynamically localized response regulator in Myxococcus xanthus. EMBO J. 2007;26:4433–44. doi: 10.1038/sj.emboj.7601877 17932488

30. Blackhart BD, Zusman DR. "Frizzy" genes of Myxococcus xanthus are involved in control of frequency of reversal of gliding motility. Proc Natl Acad Sci USA. 1985;82:8767–70. doi: 10.1073/pnas.82.24.8767 3936045

31. Guzzo M, Murray SM, Martineau E, Lhospice S, Baronian G, My L, et al. A gated relaxation oscillator mediated by FrzX controls morphogenetic movements in Myxococcus xanthus. Nat Microbiol. 2018;3:948–59. doi: 10.1038/s41564-018-0203-x 30013238

32. Kaimer C, Zusman DR. Phosphorylation-dependent localization of the response regulator FrzZ signals cell reversals in Myxococcus xanthus. Mol Microbiol. 2013;88:740–53. doi: 10.1111/mmi.12219 23551551

33. Friedrich C, Bulyha I, Søgaard-Andersen L. Outside-in assembly pathway of the type IV pilus system in Myxococcus xanthus. J Bacteriol. 2014;196:378–90. doi: 10.1128/JB.01094-13 24187092

34. Bulyha I, Schmidt C, Lenz P, Jakovljevic V, Hone A, Maier B, et al. Regulation of the type IV pili molecular machine by dynamic localization of two motor proteins. Mol Microbiol. 2009;74:691–706. doi: 10.1111/j.1365-2958.2009.06891.x 19775250

35. Chiou JG, Balasubramanian MK, Lew DJ. Cell Polarity in Yeast. Annual review of cell and developmental biology. 2017;33:77–101. doi: 10.1146/annurev-cellbio-100616-060856 28783960

36. Lutkenhaus J. The ParA/MinD family puts things in their place. Trends in microbiology. 2012;20:411–8. doi: 10.1016/j.tim.2012.05.002 22672910

37. Li R, Bowerman B. Symmetry breaking in biology. Cold Spring Harb Perspect Biol. 2010;2:a003475. doi: 10.1101/cshperspect.a003475 20300216

38. Wu CF, Lew DJ. Beyond symmetry-breaking: competition and negative feedback in GTPase regulation. Trends Cell Biol. 2013;23:476–83. doi: 10.1016/j.tcb.2013.05.003 23731999

39. Gardner TS, Cantor CR, Collins JJ. Construction of a genetic toggle switch in Escherichia coli. Nature. 2000;403:339–42. doi: 10.1038/35002131 10659857

40. Hillenbrand P, Fritz G, Gerland U. Biological Signal Processing with a Genetic Toggle Switch. PLoS ONE. 2013;8:e68345. doi: 10.1371/journal.pone.0068345 23874595

41. Simoes S, Denholm B, Azevedo D, Sotillos S, Martin P, Skaer H, et al. Compartmentalisation of Rho regulators directs cell invagination during tissue morphogenesis. Development (Cambridge, England). 2006;133:4257–67.

42. Jenkins N, Saam JR, Mango SE. CYK-4/GAP provides a localized cue to initiate anteroposterior polarity upon fertilization. Science. 2006;313:1298–301. doi: 10.1126/science.1130291 16873611

43. Iden S, Collard JG. Crosstalk between small GTPases and polarity proteins in cell polarization. Nat Rev Mol Cell Biol. 2008;9:846–59. doi: 10.1038/nrm2521 18946474

44. Hodge RG, Ridley AJ. Regulating Rho GTPases and their regulators. Nat Rev Mol Cell Biol. 2016;17:496–510. doi: 10.1038/nrm.2016.67 27301673

45. Um K, Niu S, Duman JG, Cheng JX, Tu YK, Schwechter B, et al. Dynamic control of excitatory synapse development by a Rac1 GEF/GAP regulatory complex. Dev Cell. 2014;29:701–15. doi: 10.1016/j.devcel.2014.05.011 24960694

46. Park J, Holmes WR, Lee SH, Kim HN, Kim DH, Kwak MK, et al. Mechanochemical feedback underlies coexistence of qualitatively distinct cell polarity patterns within diverse cell populations. Proc Natl Acad Sci U S A. 2017;114:E5750–e9. doi: 10.1073/pnas.1700054114 28655842

47. Holmes WR, Park J, Levchenko A, Edelstein-Keshet L. A mathematical model coupling polarity signaling to cell adhesion explains diverse cell migration patterns. PLoS computational biology. 2017;13:e1005524. doi: 10.1371/journal.pcbi.1005524 28472054

48. Hodgkin J, Kaiser D. Cell-to-cell stimulation of movement in nonmotile mutants of Myxococcus. Proc Natl Acad Sci USA. 1977;74:2938–42. doi: 10.1073/pnas.74.7.2938 16592422

49. Shi X, Wegener-Feldbrügge S, Huntley S, Hamann N, Hedderich R, Søgaard-Andersen L. Bioinformatics and Experimental Analysis of Proteins of Two-Component Systems in Myxococcus xanthus. J Bacteriol. 2008;190:613–24. doi: 10.1128/JB.01502-07 17993514

50. Sambrook J. Molecular Cloning: A Laboratory Manual, Third Edition: Cold Spring Harbor Laboratory Press; 2001.

51. Iniesta AA, García-Heras F, Abellón-Ruiz J, Gallego-García A, Elías-Arnanz M. Two Systems for Conditional Gene Expression in Myxococcus xanthus Inducible by Isopropyl-β-Thiogalactopyranoside or Vanillate. J Bacteriol. 2012;194:5875–85. doi: 10.1128/JB.01110-12 22923595

52. Schindelin J, Arganda-Carreras I, Frise E, Kaynig V, Longair M, Pietzsch T, et al. Fiji: an open-source platform for biological-image analysis. Nat Methods. 2012;9:676–82. doi: 10.1038/nmeth.2019 22743772

53. Paintdakhi A, Parry B, Campos M, Irnov I, Elf J, Surovtsev I, et al. Oufti: an integrated software package for high-accuracy, high-throughput quantitative microscopy analysis. Mol Microbiol. 2016;99:767–77. doi: 10.1111/mmi.13264 26538279

54. Baranwal J, Lhospice S, Kanade M, Chakraborty S, Gade PR, Harne S, et al. Allosteric regulation of a prokaryotic small Ras-like GTPase contributes to cell polarity oscillations in bacterial motility. PLoS Biology. 2019;17:e3000459. doi: 10.1371/journal.pbio.3000459 31560685

55. Ahnert K, Mulansky M. Odeint–Solving Ordinary Differential Equations in C++. AIP Conf Proc. 2011;1389:1586–9.

56. Fasano G, Franceschini A. A multidimensional version of the Kolmogorov–Smirnov test. Monthly Notices of the Royal Astronomical Society. 1987;225:155–70.

57. Virtanen P, Gommers R, Oliphant TE, Haberland M, Reddy T, Cournapeau D, et al. SciPy 1.0: fundamental algorithms for scientific computing in Python. Nat Methods. 2020;17:261–72.

58. Press WH, Teukolsky SA, Vetterling WT, Flannery BP. Numerical Recipes in C: The Art of Scientific Computing, Second Edition: Cambridge University Press; 1992. 994 p.

Článek vyšel v časopise

PLOS Genetics

2020 Číslo 6

Nejčtenější v tomto čísle

Tomuto tématu se dále věnují…


Zvyšte si kvalifikaci online z pohodlí domova

Citikolin v neuroprotekci a neuroregeneraci – od výzkumu do klinické praxe
nový kurz
Autoři: MUDr. Petr Výborný, CSc., FEBO

Diagnostika a léčba deprese pro ambulantní praxi
Autoři: MUDr. Jan Hubeňák, Ph.D

Význam nemocničního alert systému v době SARS-CoV-2
Autoři: doc. MUDr. Helena Lahoda Brodská, Ph.D., prim. MUDr. Václava Adámková

Snímatelné zubní náhrady a fixační krémy
Autoři: doc. MUDr. Hana Hubálková, Ph.D.

Subkutánní imunoglobuliny v léčbě sekundárních imunodeficitů (reálná praxe)

Všechny kurzy
Kurzy Doporučená témata Časopisy
Zapomenuté heslo

Nemáte účet?  Registrujte se

Zapomenuté heslo

Zadejte e-mailovou adresu se kterou jste vytvářel(a) účet, budou Vám na ni zaslány informace k nastavení nového hesla.


Nemáte účet?  Registrujte se