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Structural Basis and Functional Implications of the Membrane Pore-Formation Mechanisms of Bacterial Pore-Forming Toxins

  • Anish Kumar Mondal
  • Amritha Sreekumar
  • Nidhi Kundu
  • Reema Kathuria
  • Pratima Verma
  • Shraddha Gandhi
  • Kausik Chattopadhyay
Chapter
Part of the Advances in Experimental Medicine and Biology book series (AEMB, volume 1112)

Abstract

Pore-forming toxins (PFTs) are a distinct class of membrane-damaging protein toxins documented in a wide array of life forms ranging from bacteria to humans. PFTs are known to act as potent virulence factors of the bacterial pathogens. Bacterial PFTs are, in general, secreted as water-soluble molecules, which upon encountering target host cells assemble into transmembrane oligomeric pores, thus leading to membrane permeabilization and cell death. Interaction of the PFTs with the target host cells can also lead to plethora of cellular responses having critical implications for the bacterial pathogenesis processes, host-pathogen interactions, and host immunity. In this review, we present an overview of our current understanding of the structural aspects of the membrane pore-formation processes employed by the bacterial PFTs. We also discuss the functional implications of the PFT mode of actions, in terms of eliciting diverse cellular responses.

Keywords

Pore-forming toxin Cholesterol-dependent cytolysin Membrane Oligomerization 

Notes

Acknowledgements

We acknowledge the support through funding from the Department of Biotechnology (DBT), India [DBT Grant No. BT/PR12141/BRB/10/1343/2014; DBT Grant No. BT/HRD/NBA/37/01/2014 (x)], and also through funding under the Centre of Excellence (COE) in Frontier Areas of Science and Technology (FAST) programme of the Ministry of Human Resource Development, Government of India, in the area of protein science, design, and engineering. We also thank the Indian Institute of Science Education and Research (IISER), Mohali, for the support.

References

  1. Aguilar JL, Kulkarni R, Randis TM, Soman S, Kikuchi A, Yin Y, Ratner AJ (2009) Phosphatase-dependent regulation of epithelial mitogen-activated protein kinase responses to toxin-induced membrane pores. PLoS One 4(11):e8076.  https://doi.org/10.1371/journal.pone.0008076 CrossRefPubMedPubMedCentralGoogle Scholar
  2. Andrews NW, Almeida PE, Corrotte M (2014) Damage control: cellular mechanisms of plasma membrane repair. Trends Cell Biol 24(12):734–742.  https://doi.org/10.1016/j.tcb.2014.07.008 CrossRefPubMedPubMedCentralGoogle Scholar
  3. Babiychuk EB, Monastyrskaya K, Potez S, Draeger A (2011) Blebbing confers resistance against cell lysis. Cell Death Differ 18(1):80–89.  https://doi.org/10.1038/cdd.2010.81 CrossRefPubMedGoogle Scholar
  4. Bischofberger M, Iacovache I, van der Goot FG (2012) Pathogenic pore-forming proteins: function and host response. Cell Host Microbe 12(3):266–275.  https://doi.org/10.1016/j.chom.2012.08.005 CrossRefPubMedGoogle Scholar
  5. Cassidy SK, O’Riordan MX (2013) More than a pore: the cellular response to cholesterol-dependent cytolysins. Toxins 5(4):618–636.  https://doi.org/10.3390/toxins5040618 CrossRefPubMedPubMedCentralGoogle Scholar
  6. Chattopadhyay K, Bhattacharyya D, Banerjee KK (2002) Vibrio cholerae hemolysin. Implication of amphiphilicity and lipid-induced conformational change for its pore-forming activity. Eur J Biochem 269(17):4351–4358CrossRefGoogle Scholar
  7. Collier RJ (1975) Diphtheria toxin: mode of action and structure. Bacteriol Rev 39(1):54–85PubMedPubMedCentralGoogle Scholar
  8. Dal Peraro M, van der Goot FG (2016) Pore-forming toxins: ancient, but never really out of fashion. Nat Rev Microbiol 14(2):77–92.  https://doi.org/10.1038/nrmicro.2015.3 CrossRefPubMedGoogle Scholar
  9. De Haan L, Hirst TR (2004) Cholera toxin: a paradigm for multi-functional engagement of cellular mechanisms (review). Mol Membr Biol 21(2):77–92.  https://doi.org/10.1080/09687680410001663267 CrossRefPubMedGoogle Scholar
  10. De S, Olson R (2011) Crystal structure of the Vibrio cholerae cytolysin heptamer reveals common features among disparate pore-forming toxins. Proc Natl Acad Sci U S A 108(18):7385–7390.  https://doi.org/10.1073/pnas.1017442108 CrossRefPubMedPubMedCentralGoogle Scholar
  11. Diep DB, Nelson KL, Raja SM, Pleshak EN, Buckley JT (1998) Glycosylphosphatidylinositol anchors of membrane glycoproteins are binding determinants for the channel-forming toxin aerolysin. J Biol Chem 273(4):2355–2360CrossRefGoogle Scholar
  12. Dragneva Y, Anuradha CD, Valeva A, Hoffmann A, Bhakdi S, Husmann M (2001) Subcytocidal attack by staphylococcal alpha-toxin activates NF-kappaB and induces interleukin-8 production. Infect Immun 69(4):2630–2635.  https://doi.org/10.1128/IAI.69.4.2630-2635.2001 CrossRefPubMedPubMedCentralGoogle Scholar
  13. DuMont AL, Torres VJ (2014) Cell targeting by the Staphylococcus aureus pore-forming toxins: it’s not just about lipids. Trends Microbiol 22(1):21–27.  https://doi.org/10.1016/j.tim.2013.10.004 CrossRefPubMedGoogle Scholar
  14. Fahie M, Romano FB, Chisholm C, Heuck AP, Zbinden M, Chen M (2013) A non-classical assembly pathway of Escherichia coli pore-forming toxin cytolysin a. J Biol Chem 288(43):31042–31051.  https://doi.org/10.1074/jbc.M113.475350 CrossRefPubMedPubMedCentralGoogle Scholar
  15. Farrand AJ, LaChapelle S, Hotze EM, Johnson AE, Tweten RK (2010) Only two amino acids are essential for cytolytic toxin recognition of cholesterol at the membrane surface. Proc Natl Acad Sci U S A 107(9):4341–4346.  https://doi.org/10.1073/pnas.0911581107 CrossRefPubMedPubMedCentralGoogle Scholar
  16. Feil SC, Ascher DB, Kuiper MJ, Tweten RK, Parker MW (2014) Structural studies of Streptococcus pyogenes streptolysin O provide insights into the early steps of membrane penetration. J Mol Biol 426(4):785–792.  https://doi.org/10.1016/j.jmb.2013.11.020 CrossRefPubMedGoogle Scholar
  17. Geny B, Popoff MR (2006) Bacterial protein toxins and lipids: pore formation or toxin entry into cells. Biol Cell 98(11):667–678.  https://doi.org/10.1042/BC20050082 CrossRefPubMedGoogle Scholar
  18. Giddings KS, Zhao J, Sims PJ, Tweten RK (2004) Human CD59 is a receptor for the cholesterol-dependent cytolysin intermedilysin. Nat Struct Mol Biol 11(12):1173–1178.  https://doi.org/10.1038/nsmb862 CrossRefPubMedGoogle Scholar
  19. Gilbert RJ, Dalla Serra M, Froelich CJ, Wallace MI, Anderluh G (2014) Membrane pore formation at protein-lipid interfaces. Trends Biochem Sci 39(11):510–516.  https://doi.org/10.1016/j.tibs.2014.09.002 CrossRefPubMedGoogle Scholar
  20. Gouaux E (1997) Channel-forming toxins: tales of transformation. Curr Opin Struct Biol 7(4):566–573CrossRefGoogle Scholar
  21. Gutierrez MG, Saka HA, Chinen I, Zoppino FC, Yoshimori T, Bocco JL, Colombo MI (2007) Protective role of autophagy against Vibrio cholerae cytolysin, a pore-forming toxin from V. cholerae. Proc Natl Acad Sci U S A 104(6):1829–1834.  https://doi.org/10.1073/pnas.0601437104 CrossRefPubMedPubMedCentralGoogle Scholar
  22. Heuck AP, Moe PC, Johnson BB (2010) The cholesterol-dependent cytolysin family of gram-positive bacterial toxins. Subcell Biochem 51:551–577.  https://doi.org/10.1007/978-90-481-8622-8_20 CrossRefPubMedGoogle Scholar
  23. Heuck AP, Tweten RK, Johnson AE (2001) Beta-barrel pore-forming toxins: intriguing dimorphic proteins. Biochemistry 40(31):9065–9073CrossRefGoogle Scholar
  24. Hong Y, Ohishi K, Inoue N, Kang JY, Shime H, Horiguchi Y, van der Goot FG, Sugimoto N, Kinoshita T (2002) Requirement of N-glycan on GPI-anchored proteins for efficient binding of aerolysin but not Clostridium septicum alpha-toxin. EMBO J 21(19):5047–5056CrossRefGoogle Scholar
  25. Hunt S, Green J, Artymiuk PJ (2010) Hemolysin E (HlyE, ClyA, SheA) and related toxins. Adv Exp Med Biol 677:116–126CrossRefGoogle Scholar
  26. Husmann M, Beckmann E, Boller K, Kloft N, Tenzer S, Bobkiewicz W, Neukirch C, Bayley H, Bhakdi S (2009) Elimination of a bacterial pore-forming toxin by sequential endocytosis and exocytosis. FEBS Lett 583(2):337–344.  https://doi.org/10.1016/j.febslet.2008.12.028 CrossRefPubMedGoogle Scholar
  27. Huyet J, Naylor CE, Savva CG, Gibert M, Popoff MR, Basak AK (2013) Structural insights into Clostridium perfringens delta toxin pore formation. PLoS One 8(6):e66673.  https://doi.org/10.1371/journal.pone.0066673 CrossRefPubMedPubMedCentralGoogle Scholar
  28. Iacovache I, Bischofberger M, van der Goot FG (2010) Structure and assembly of pore-forming proteins. Curr Opin Struct Biol 20(2):241–246.  https://doi.org/10.1016/j.sbi.2010.01.013 CrossRefPubMedGoogle Scholar
  29. Idone V, Tam C, Goss JW, Toomre D, Pypaert M, Andrews NW (2008) Repair of injured plasma membrane by rapid Ca2+−dependent endocytosis. J Cell Biol 180(5):905–914.  https://doi.org/10.1083/jcb.200708010 CrossRefPubMedPubMedCentralGoogle Scholar
  30. Johnson BB, Heuck AP (2014) Perfringolysin O structure and mechanism of pore formation as a paradigm for cholesterol-dependent cytolysins. Subcell Biochem 80:63–81.  https://doi.org/10.1007/978-94-017-8881-6_5 CrossRefPubMedPubMedCentralGoogle Scholar
  31. Kennedy CL, Smith DJ, Lyras D, Chakravorty A, Rood JI (2009) Programmed cellular necrosis mediated by the pore-forming alpha-toxin from Clostridium septicum. PLoS Pathog 5(7):e1000516.  https://doi.org/10.1371/journal.ppat.1000516 CrossRefPubMedPubMedCentralGoogle Scholar
  32. Khilwani B, Chattopadhyay K (2015) Signaling beyond punching holes: modulation of cellular responses by Vibrio cholerae Cytolysin. Toxins 7(8):3344–3358.  https://doi.org/10.3390/toxins7083344 CrossRefPubMedPubMedCentralGoogle Scholar
  33. Khilwani B, Mukhopadhaya A, Chattopadhyay K (2015) Transmembrane oligomeric form of Vibrio cholerae cytolysin triggers TLR2/TLR6-dependent proinflammatory responses in monocytes and macrophages. Biochem J 466(1):147–161.  https://doi.org/10.1042/BJ20140718 CrossRefPubMedGoogle Scholar
  34. Koster S, van Pee K, Hudel M, Leustik M, Rhinow D, Kuhlbrandt W, Chakraborty T, Yildiz O (2014) Crystal structure of listeriolysin O reveals molecular details of oligomerization and pore formation. Nat Commun 5:3690.  https://doi.org/10.1038/ncomms4690 CrossRefPubMedGoogle Scholar
  35. Kundu N, Tichkule S, Pandit SB, Chattopadhyay K (2017) Disulphide bond restrains the C-terminal region of thermostable direct hemolysin during folding to promote oligomerization. Biochem J 474(2):317–331.  https://doi.org/10.1042/BCJ20160728 CrossRefPubMedGoogle Scholar
  36. Lakey JH, Massotte D, Heitz F, Dasseux JL, Faucon JF, Parker MW, Pattus F (1991) Membrane insertion of the pore-forming domain of colicin A. A spectroscopic study. Eur J Biochem 196(3):599–607CrossRefGoogle Scholar
  37. Lakey JH, Slatin SL (2001) Pore-forming colicins and their relatives. Curr Top Microbiol Immunol 257:131–161PubMedGoogle Scholar
  38. Lesieur C, Vecsey-Semjen B, Abrami L, Fivaz M, Gisou van der Goot F (1997) Membrane insertion: the strategies of toxins (review). Mol Membr Biol 14(2):45–64CrossRefGoogle Scholar
  39. Levan S, De S, Olson R (2013) Vibrio cholerae cytolysin recognizes the heptasaccharide core of complex N-glycans with nanomolar affinity. J Mol Biol 425(5):944–957.  https://doi.org/10.1016/j.jmb.2012.12.016 CrossRefPubMedGoogle Scholar
  40. Montoya M, Gouaux E (2003) Beta-barrel membrane protein folding and structure viewed through the lens of alpha-hemolysin. Biochim Biophys Acta 1609(1):19–27CrossRefGoogle Scholar
  41. Morgan BP, Boyd C, Bubeck D (2017) Molecular cell biology of complement membrane attack. Semin Cell Dev Biol 72:124–132.  https://doi.org/10.1016/j.semcdb.2017.06.009 CrossRefPubMedGoogle Scholar
  42. Mueller M, Grauschopf U, Maier T, Glockshuber R, Ban N (2009) The structure of a cytolytic alpha-helical toxin pore reveals its assembly mechanism. Nature 459(7247):726–730.  https://doi.org/10.1038/nature08026 CrossRefPubMedGoogle Scholar
  43. Nelson KL, Brodsky RA, Buckley JT (1999) Channels formed by subnanomolar concentrations of the toxin aerolysin trigger apoptosis of T lymphomas. Cell Microbiol 1(1):69–74CrossRefGoogle Scholar
  44. Oh KJ, Senzel L, Collier RJ, Finkelstein A (1999) Translocation of the catalytic domain of diphtheria toxin across planar phospholipid bilayers by its own T domain. Proc Natl Acad Sci U S A 96(15):8467–8470CrossRefGoogle Scholar
  45. Parker MW, Pattus F, Tucker AD, Tsernoglou D (1989) Structure of the membrane-pore-forming fragment of colicin A. Nature 337(6202):93–96.  https://doi.org/10.1038/337093a0 CrossRefPubMedGoogle Scholar
  46. Paul K, Chattopadhyay K (2012) Single point mutation in Vibrio cholerae cytolysin compromises the membrane pore-formation mechanism of the toxin. FEBS J 279(21):4039–4051.  https://doi.org/10.1111/j.1742-4658.2012.08809.x CrossRefPubMedGoogle Scholar
  47. Podobnik M, Kisovec M, Anderluh G (2017) Molecular mechanism of pore formation by aerolysin-like proteins. Philos Trans R Soc Lond Ser B Biol Sci 372(1726):1.  https://doi.org/10.1098/rstb.2016.0209 CrossRefGoogle Scholar
  48. Polekhina G, Giddings KS, Tweten RK, Parker MW (2005) Insights into the action of the superfamily of cholesterol-dependent cytolysins from studies of intermedilysin. Proc Natl Acad Sci U S A 102(3):600–605.  https://doi.org/10.1073/pnas.0403229101 CrossRefPubMedPubMedCentralGoogle Scholar
  49. Rai AK, Chattopadhyay K (2015a) Revisiting the membrane interaction mechanism of a membrane-damaging beta-barrel pore-forming toxin Vibrio cholerae cytolysin. Mol Microbiol 97(6):1051–1062.  https://doi.org/10.1111/mmi.13084 CrossRefPubMedGoogle Scholar
  50. Rai AK, Chattopadhyay K (2015b) Vibrio cholerae cytolysin: structure-function mechanism of an atypical beta-barrel pore-forming toxin. Adv Exp Med Biol 842:109–125.  https://doi.org/10.1007/978-3-319-11280-0_7 CrossRefPubMedGoogle Scholar
  51. Rai AK, Paul K, Chattopadhyay K (2013) Functional mapping of the lectin activity site on the beta-prism domain of vibrio cholerae cytolysin: implications for the membrane pore-formation mechanism of the toxin. J Biol Chem 288(3):1665–1673.  https://doi.org/10.1074/jbc.M112.430181 CrossRefPubMedGoogle Scholar
  52. Reboul CF, Whisstock JC, Dunstone MA (2016) Giant MACPF/CDC pore forming toxins: a class of their own. Biochim Biophys Acta 1858(3):475–486.  https://doi.org/10.1016/j.bbamem.2015.11.017 CrossRefPubMedGoogle Scholar
  53. Ridley H, Johnson CL, Lakey JH (2010) Interfacial interactions of pore-forming colicins. Adv Exp Med Biol 677:81–90CrossRefGoogle Scholar
  54. Rojko N, Dalla Serra M, Macek P, Anderluh G (2016) Pore formation by actinoporins, cytolysins from sea anemones. Biochim Biophys Acta 1858(3):446–456.  https://doi.org/10.1016/j.bbamem.2015.09.007 CrossRefPubMedGoogle Scholar
  55. Saha N, Banerjee KK (1997) Carbohydrate-mediated regulation of interaction of Vibrio cholerae hemolysin with erythrocyte and phospholipid vesicle. J Biol Chem 272(1):162–167CrossRefGoogle Scholar
  56. Tweten RK, Hotze EM, Wade KR (2015) The unique molecular choreography of giant pore formation by the cholesterol-dependent cytolysins of Gram-positive bacteria. Annu Rev Microbiol 69:323–340.  https://doi.org/10.1146/annurev-micro-091014-104233 CrossRefPubMedGoogle Scholar
  57. van der Goot FG, Gonzalez-Manas JM, Lakey JH, Pattus F (1991) A ‘molten-globule’ membrane-insertion intermediate of the pore-forming domain of colicin A. Nature 354(6352):408–410.  https://doi.org/10.1038/354408a0 CrossRefPubMedGoogle Scholar
  58. Wallace AJ, Stillman TJ, Atkins A, Jamieson SJ, Bullough PA, Green J, Artymiuk PJ (2000) E. coli hemolysin E (HlyE, ClyA, SheA): X-ray crystal structure of the toxin and observation of membrane pores by electron microscopy. Cell 100(2):265–276CrossRefGoogle Scholar
  59. Westphal D, Dewson G, Czabotar PE, Kluck RM (2011) Molecular biology of Bax and Bak activation and action. Biochim Biophys Acta 1813(4):521–531.  https://doi.org/10.1016/j.bbamcr.2010.12.019 CrossRefPubMedGoogle Scholar
  60. Wiener M, Freymann D, Ghosh P, Stroud RM (1997) Crystal structure of colicin Ia. Nature 385(6615):461–464.  https://doi.org/10.1038/385461a0 CrossRefPubMedGoogle Scholar
  61. Wiles TJ, Dhakal BK, Eto DS, Mulvey MA (2008) Inactivation of host Akt/protein kinase B signaling by bacterial pore-forming toxins. Mol Biol Cell 19(4):1427–1438.  https://doi.org/10.1091/mbc.E07-07-0638 CrossRefPubMedPubMedCentralGoogle Scholar
  62. Wilke GA, Bubeck Wardenburg J (2010) Role of a disintegrin and metalloprotease 10 in Staphylococcus aureus alpha-hemolysin-mediated cellular injury. Proc Natl Acad Sci U S A 107(30):13473–13478.  https://doi.org/10.1073/pnas.1001815107 CrossRefPubMedPubMedCentralGoogle Scholar
  63. Xu C, Wang BC, Yu Z, Sun M (2014) Structural insights into Bacillus thuringiensis Cry, Cyt and parasporin toxins. Toxins 6(9):2732–2770.  https://doi.org/10.3390/toxins6092732 CrossRefPubMedPubMedCentralGoogle Scholar
  64. Yanagihara I, Nakahira K, Yamane T, Kaieda S, Mayanagi K, Hamada D, Fukui T, Ohnishi K, Kajiyama S, Shimizu T, Sato M, Ikegami T, Ikeguchi M, Honda T, Hashimoto H (2010) Structure and functional characterization of Vibrio parahaemolyticus thermostable direct hemolysin. J Biol Chem 285(21):16267–16274.  https://doi.org/10.1074/jbc.M109.074526 CrossRefPubMedPubMedCentralGoogle Scholar
  65. Zakharov SD, Cramer WA (2002) Colicin crystal structures: pathways and mechanisms for colicin insertion into membranes. Biochim Biophys Acta 1565(2):333–346CrossRefGoogle Scholar
  66. Zhang D, Takahashi J, Seno T, Tani Y, Honda T (1999) Analysis of receptor for Vibrio cholerae El tor hemolysin with a monoclonal antibody that recognizes glycophorin B of human erythrocyte membrane. Infect Immun 67(10):5332–5337PubMedPubMedCentralGoogle Scholar
  67. Zilnyte M, Venclovas C, Zvirbliene A, Pleckaityte M (2015) The cytolytic activity of vaginolysin strictly depends on cholesterol and is potentiated by human CD59. Toxins 7(1):110–128.  https://doi.org/10.3390/toxins7010110 CrossRefPubMedPubMedCentralGoogle Scholar
  68. Zitzer A, Bittman R, Verbicky CA, Erukulla RK, Bhakdi S, Weis S, Valeva A, Palmer M (2001) Coupling of cholesterol and cone-shaped lipids in bilayers augments membrane permeabilization by the cholesterol-specific toxins streptolysin O and Vibrio cholerae cytolysin. J Biol Chem 276(18):14628–14633.  https://doi.org/10.1074/jbc.M100241200. M100241200 [pii]CrossRefPubMedGoogle Scholar
  69. Zitzer A, Westover EJ, Covey DF, Palmer M (2003) Differential interaction of the two cholesterol-dependent, membrane-damaging toxins, streptolysin O and Vibrio cholerae cytolysin, with enantiomeric cholesterol. FEBS Lett 553(3):229–231CrossRefGoogle Scholar

Copyright information

© Springer Nature Singapore Pte Ltd. 2018

Authors and Affiliations

  • Anish Kumar Mondal
    • 1
  • Amritha Sreekumar
    • 1
  • Nidhi Kundu
    • 1
  • Reema Kathuria
    • 1
  • Pratima Verma
    • 1
  • Shraddha Gandhi
    • 1
  • Kausik Chattopadhyay
    • 1
  1. 1.Centre for Protein Science, Design and Engineering, Department of Biological SciencesIndian Institute of Science Education and Research (IISER) MohaliMohaliIndia

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