Medical Microbiology and Immunology

, Volume 201, Issue 4, pp 419–426 | Cite as

Pore-forming bacterial toxins and antimicrobial peptides as modulators of ADAM function

  • Karina ReissEmail author
  • Sucharit Bhakdi


Membrane-perturbating proteins and peptides are widespread agents in biology. Pore-forming bacterial toxins represent major virulence factors of pathogenic microorganisms. Membrane-damaging peptides constitute important antimicrobial effectors of innate immunity. Membrane perturbation can incur multiple responses in mammalian cells. The present discussion will focus on the interplay between membrane-damaging agents and the function of cell-bound metalloproteinases of the ADAM family. These transmembrane enzymes have emerged as the major proteinase family that mediate the proteolytic release of membrane-associated proteins, a process designated as “shedding”. They liberate a large spectrum of functionally active molecules including inflammatory cytokines, growth factor receptors and cell adhesion molecules, thereby regulating such vital cellular functions as cell–cell adhesion, cell proliferation and cell migration. ADAM activation may constitute part of the cellular recovery machinery on the one hand, but likely also promotes inflammatory processes on the other. The mechanisms underlying ADAM activation and the functional consequences thereof are currently the subject of intensive research. Attention here is drawn to the possible involvement of purinergic receptors and ceramide generation in the context of ADAM activation following membrane perturbation by membrane-active agents.


Bacterial toxins Antimicrobial peptides Metalloproteinase ADAMs EGFR 



This work was supported by the Deutsche Forschungsgemeinschaft, Sonderforschungsbereich 490 (S.B.), CRC877 (K.R.) and the Cluster of Excellence “Inflammation at Interfaces” (K.R.).


The references marked with an asterisk result from the work within projects of the collaborative research centre (SFB) 490

  1. 1.
    Pan D, Rubin GM (1997) Kuzbanian controls proteolytic processing of notch and mediates lateral inhibition during drosophila and vertebrate neurogenesis. Cell 90:271–280PubMedCrossRefGoogle Scholar
  2. 2.
    Huang X, Huang P, Robinson MK, Stern MJ, Jin Y (2003) UNC-71, a disintegrin and metalloprotease (ADAM) protein, regulates motor axon guidance and sex myoblast migration in C. elegans. Development 130:3147–3161PubMedCrossRefGoogle Scholar
  3. 3.
    Nakamura T, Abe H, Hirata A, Shimoda C (2004) ADAM family protein Mde10 is essential for development of spore envelopes in the fission yeast Schizosaccharomyces pombe. Eukaryot Cell 3:27–39PubMedCrossRefGoogle Scholar
  4. 4.
    Rose-John S, Heinrich PC (1994) Soluble receptors for cytokines and growth factors: generation and biological function. Biochem J 300(Pt 2):281–290PubMedGoogle Scholar
  5. 5.
    Reiss K, Saftig P (2009) The “a disintegrin and metalloprotease” (ADAM) family of sheddases: physiological and cellular functions. Semin Cell Dev Biol 20:126–137PubMedCrossRefGoogle Scholar
  6. 6.
    Pruessmeyer J, Ludwig A (2009) The good, the bad and the ugly substrates for ADAM10 and ADAM17 in brain pathology, inflammation and cancer. Semin Cell Dev Biol 20:164–174PubMedCrossRefGoogle Scholar
  7. 7.
    Edwards DR, Handsley MM, Pennington CJ (2008) The ADAM metalloproteinases. Mol Aspects Med 29:258–289PubMedCrossRefGoogle Scholar
  8. 8.
    Saftig P, Reiss K (2011) The “a disintegrin and metalloproteases” ADAM10 and ADAM17: novel drug targets with therapeutic potential? Eur J Cell Biol 90:527–535PubMedCrossRefGoogle Scholar
  9. 9.
    Hartmann D, de Strooper B, Serneels L, Craessaerts K, Herreman A, Annaert W, Umans L, Lubke T, Lena IA, von Figura K et al (2002) The disintegrin/metalloprotease ADAM 10 is essential for notch signalling but not for alpha-secretase activity in fibroblasts. Hum Mol Genet 11:2615–2624PubMedCrossRefGoogle Scholar
  10. 10.
    Peschon JJ, Slack JL, Reddy P, Stocking KL, Sunnarborg SW, Lee DC, Russell WE, Castner BJ, Johnson RS, Fitzner JN et al (1998) An essential role for ectodomain shedding in mammalian development. Science 282:1281–1284PubMedCrossRefGoogle Scholar
  11. 11.
    Maretzky T, Reiss K, Ludwig A, Buchholz J, Scholz F, Proksch E, de Strooper B, Hartmann D, Saftig P (2005) ADAM10 mediates E-cadherin shedding and regulates epithelial cell–cell adhesion, migration, and beta-catenin translocation. Proc Natl Acad Sci U.S.A 102:9182–9187PubMedCrossRefGoogle Scholar
  12. 12.
    Reiss K, Maretzky T, Ludwig A, Tousseyn T, de Strooper B, Hartmann D, Saftig P (2005) ADAM10 cleavage of N-cadherin and regulation of cell–cell adhesion and beta-catenin nuclear signalling. EMBO J 24:742–752PubMedCrossRefGoogle Scholar
  13. 13.
    Nagano O, Murakami D, Hartmann D, de Strooper B, Saftig P, Iwatsubo T, Nakajima M, Shinohara M, Saya H (2004) Cell-matrix interaction via CD44 is independently regulated by different metalloproteinases activated in response to extracellular Ca(2 +) influx and PKC activation. J Cell Biol 165:893–902PubMedCrossRefGoogle Scholar
  14. 14.
    Schulz B, Pruessmeyer J, Maretzky T, Ludwig A, Blobel CP, Saftig P, Reiss K (2008) ADAM10 regulates endothelial permeability and T-Cell transmigration by proteolysis of vascular endothelial cadherin. Circ Res 102:1192–1201PubMedCrossRefGoogle Scholar
  15. 15.
    Hundhausen C, Misztela D, Berkhout TA, Broadway N, Saftig P, Reiss K, Hartmann D, Fahrenholz F, Postina R, Matthews V et al (2003) The disintegrin-like metalloproteinase ADAM10 is involved in constitutive cleavage of CX3CL1 (fractalkine) and regulates CX3CL1-mediated cell–cell adhesion. Blood 102:1186–1195PubMedCrossRefGoogle Scholar
  16. 16.
    Abel S, Hundhausen C, Mentlein R, Schulte A, Berkhout TA, Broadway N, Hartmann D, Sedlacek R, Dietrich S, Muetze B et al (2004) The transmembrane CXC-chemokine ligand 16 is induced by IFN-gamma and TNF-alpha and shed by the activity of the disintegrin-like metalloproteinase ADAM10. J Immunol 172:6362–6372PubMedGoogle Scholar
  17. 17.
    Sahin U, Weskamp G, Kelly K, Zhou HM, Higashiyama S, Peschon J, Hartmann D, Saftig P, Blobel CP (2004) Distinct roles for ADAM10 and ADAM17 in ectodomain shedding of six EGFR ligands. J Cell Biol 164:769–779PubMedCrossRefGoogle Scholar
  18. 18.
    Prenzel N, Zwick E, Daub H, Leserer M, Abraham R, Wallasch C, Ullrich A (1999) EGF receptor transactivation by G-protein-coupled receptors requires metalloproteinase cleavage of proHB-EGF. Nature 402:884–888PubMedGoogle Scholar
  19. 19.
    Yan Y, Shirakabe K, Werb Z (2002) The metalloprotease Kuzbanian (ADAM10) mediates the transactivation of EGF receptor by G protein-coupled receptors. J Cell Biol 158:221–226PubMedCrossRefGoogle Scholar
  20. 20.
    Blobel CP, Carpenter G, Freeman M (2009) The role of protease activity in ErbB biology. Exp Cell Res 315:671–682PubMedCrossRefGoogle Scholar
  21. 21.
    Swendeman S, Mendelson K, Weskamp G, Horiuchi K, Deutsch U, Scherle P, Hooper A, Rafii S, Blobel CP (2008) VEGF-A stimulates ADAM17-dependent shedding of VEGFR2 and crosstalk between VEGFR2 and ERK signaling. Circ Res 103:916–918PubMedCrossRefGoogle Scholar
  22. 22.
    Maretzky T, Evers A, Zhou W, Swendeman SL, Wong PM, Rafii S, Reiss K, Blobel CP (2011) Migration of growth factor-stimulated epithelial and endothelial cells depends on EGFR transactivation by ADAM17. Nat Commun 2:229PubMedCrossRefGoogle Scholar
  23. 23.
    Killock DJ, Ivetic A (2010) The cytoplasmic domains of TNFalpha-converting enzyme (TACE/ADAM17) and L-selectin are regulated differently by p38 MAPK and PKC to promote ectodomain shedding. Biochem J 428:293–304PubMedCrossRefGoogle Scholar
  24. 24.
    Soond SM, Everson B, Riches DW, Murphy G (2005) ERK-mediated phosphorylation of Thr735 in TNFalpha-converting enzyme and its potential role in TACE protein trafficking. J Cell Sci 118:2371–2380PubMedCrossRefGoogle Scholar
  25. 25.
    Horiuchi K, Le Gall S, Schulte M, Yamaguchi T, Reiss K, Murphy G, Toyama Y, Hartmann D, Saftig P, Blobel CP (2007) Substrate selectivity of epidermal growth factor-receptor ligand sheddases and their regulation by phorbol esters and calcium influx. Mol Biol Cell 18:176–188PubMedCrossRefGoogle Scholar
  26. 26.
    Diaz-Rodriguez E, Montero JC, Esparis-Ogando A, Yuste L, Pandiella A (2002) Extracellular signal-regulated kinase phosphorylates tumor necrosis factor alpha-converting enzyme at threonine 735: a potential role in regulated shedding. Mol Biol Cell 13:2031–2044PubMedCrossRefGoogle Scholar
  27. 27.
    Fan H, Turck CW, Derynck R (2003) Characterization of growth factor-induced serine phosphorylation of tumor necrosis factor-alpha converting enzyme and of an alternatively translated polypeptide. J Biol Chem 278:18617–18627PubMedCrossRefGoogle Scholar
  28. 28.
    Xu P, Derynck R (2010) Direct activation of TACE-mediated ectodomain shedding by p38 MAP kinase regulates EGF receptor-dependent cell proliferation. Mol Cell 37:551–566PubMedCrossRefGoogle Scholar
  29. 29.
    Reddy P, Slack JL, Davis R, Cerretti DP, Kozlosky CJ, Blanton RA, Shows D, Peschon JJ, Black RA (2000) Functional analysis of the domain structure of tumor necrosis factor-alpha converting enzyme. J Biol Chem 275:14608–14614PubMedCrossRefGoogle Scholar
  30. 30.
    Doedens JR, Mahimkar RM, Black RA (2003) TACE/ADAM-17 enzymatic activity is increased in response to cellular stimulation. Biochem Biophys Res Commun 308:331–338PubMedCrossRefGoogle Scholar
  31. 31.
    Lorenzen I, Trad A, Grotzinger J (2011) Multimerisation of A disintegrin and metalloprotease protein-17 (ADAM17) is mediated by its EGF-like domain. Biochem Biophys Res Commun 415:330–336PubMedCrossRefGoogle Scholar
  32. 32.
    Xu P, Liu J, Sakaki-Yumoto M, Derynck R (2012) TACE activation by MAPK-mediated regulation of cell surface dimerization and TIMP3 association. Sci Signal 5:ra34Google Scholar
  33. 33.
    Le Gall SM, Maretzky T, Issuree PD, Niu XD, Reiss K, Saftig P, Khokha R, Lundell D, Blobel CP (2010) ADAM17 is regulated by a rapid and reversible mechanism that controls access to its catalytic site. J Cell Sci 123:3913–3922PubMedCrossRefGoogle Scholar
  34. 34.
    *Reiss K, Cornelsen I, Husmann M, Gimpl G, Bhakdi S (2011) Unsaturated fatty acids drive disintegrin and metalloproteinase (ADAM)-dependent cell adhesion, proliferation, and migration by modulating membrane fluidity. J Biol Chem 286:26931–26942PubMedCrossRefGoogle Scholar
  35. 35.
    Bhakdi S, Tranum-Jensen J (1987) Damage to mammalian cells by proteins that form transmembrane pores. Rev Physiol Biochem Pharmacol 107:147–223PubMedCrossRefGoogle Scholar
  36. 36.
    Gonzalez MR, Bischofberger M, Pernot L, van der Goot FG, Freche B (2008) Bacterial pore-forming toxins: the (w)hole story? Cell Mol Life Sci 65:493–507PubMedCrossRefGoogle Scholar
  37. 37.
    Bhakdi S, Bayley H, Valeva A, Walev I, Walker B, Kehoe M, Palmer M (1996) Staphylococcal alpha-toxin, streptolysin-O, and Escherichia coli hemolysin: prototypes of pore-forming bacterial cytolysins. Arch Microbiol 165:73–79PubMedCrossRefGoogle Scholar
  38. 38.
    Bhakdi S, Tranum-Jensen J (1991) Alpha-toxin of staphylococcus aureus. Microbiol Rev 55:733–751PubMedGoogle Scholar
  39. 39.
    Hildebrand A, Pohl M, Bhakdi S (1991) Staphylococcus aureus alpha-toxin. Dual mechanism of binding to target cells. J Biol Chem 266:17195–17200PubMedGoogle Scholar
  40. 40.
    Valeva A, Walev I, Pinkernell M, Walker B, Bayley H, Palmer M, Bhakdi S (1997) Transmembrane beta-barrel of staphylococcal alpha-toxin forms in sensitive but not in resistant cells. Proc Natl Acad Sci U.S.A 94:11607–11611PubMedCrossRefGoogle Scholar
  41. 41.
    *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 583:337–344PubMedCrossRefGoogle Scholar
  42. 42.
    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 180:905–914PubMedCrossRefGoogle Scholar
  43. 43.
    Rosado CJ, Buckle AM, Law RH, Butcher RE, Kan WT, Bird CH, Ung K, Browne KA, Baran K, Bashtannyk-Puhalovich TA et al (2007) A common fold mediates vertebrate defense and bacterial attack. Science 317:1548–1551PubMedCrossRefGoogle Scholar
  44. 44.
    Hadders MA, Beringer DX, Gros P (2007) Structure of C8alpha-MACPF reveals mechanism of membrane attack in complement immune defense. Science 317:1552–1554PubMedCrossRefGoogle Scholar
  45. 45.
    Gilbert RJ (2010) Cholesterol-dependent cytolysins. Adv Exp Med Biol 677:56–66PubMedCrossRefGoogle Scholar
  46. 46.
    *Valeva A, Walev I, Kemmer H, Weis S, Siegel I, Boukhallouk F, Wassenaar TM, Chavakis T, Bhakdi S (2005) Binding of Escherichia coli hemolysin and activation of the target cells is not receptor-dependent. J Biol Chem 280:36657–36663PubMedCrossRefGoogle Scholar
  47. 47.
    Uhlen P, Laestadius A, Jahnukainen T, Soderblom T, Backhed F, Celsi G, Brismar H, Normark S, Aperia A, Richter-Dahlfors A (2000) Alpha-haemolysin of uropathogenic E. coli induces Ca2 + oscillations in renal epithelial cells. Nature 405:694–697PubMedCrossRefGoogle Scholar
  48. 48.
    *Koschinski A, Repp H, Unver B, Dreyer F, Brockmeier D, Valeva A, Bhakdi S, Walev I (2006) Why Escherichia coli alpha-hemolysin induces calcium oscillations in mammalian cells–the pore is on its own. FASEB J 20:973–975PubMedCrossRefGoogle Scholar
  49. 49.
    Brogden KA (2005) Antimicrobial peptides: pore formers or metabolic inhibitors in bacteria? Nat Rev Microbiol 3:238–250PubMedCrossRefGoogle Scholar
  50. 50.
    Duclohier H (2010) Antimicrobial peptides and peptaibols, substitutes for conventional antibiotics. Curr Pharm Des 16:3212–3223PubMedCrossRefGoogle Scholar
  51. 51.
    Park Y, Hahm KS (2005) Antimicrobial peptides (AMPs): peptide structure and mode of action. J Biochem Mol Biol 38:507–516PubMedCrossRefGoogle Scholar
  52. 52.
    Lohner K, Blondelle SE (2005) Molecular mechanisms of membrane perturbation by antimicrobial peptides and the use of biophysical studies in the design of novel peptide antibiotics. Comb Chem High Throughput Screen 8:241–256PubMedCrossRefGoogle Scholar
  53. 53.
    Wilke GA, Bubeck WJ (2010) Role of a disintegrin and metalloprotease 10 in staphylococcus aureus alpha-hemolysin-mediated cellular injury. Proc Natl Acad Sci U.S.A 107:13473–13478PubMedCrossRefGoogle Scholar
  54. 54.
    Inoshima I, Inoshima N, Wilke GA, Powers ME, Frank KM, Wang Y, Bubeck WJ (2011) A staphylococcus aureus pore-forming toxin subverts the activity of ADAM10 to cause lethal infection in mice. Nat Med 17:1310–1314PubMedCrossRefGoogle Scholar
  55. 55.
    Inoshima N, Wang Y, Wardenburg JB (2012) Genetic requirement for ADAM10 in severe Staphylococcus aureus skin infection. J Invest Dermatol 132:1513–1516PubMedCrossRefGoogle Scholar
  56. 56.
    Walev I, Vollmer P, Palmer M, Bhakdi S, Rose-John S (1996) Pore-forming toxins trigger shedding of receptors for interleukin 6 and lipopolysaccharide. Proc Natl Acad Sci U.S.A 93:7882–7887PubMedCrossRefGoogle Scholar
  57. 57.
    *Haugwitz U, Bobkiewicz W, Han SR, Beckmann E, Veerachato G, Shaid S, Biehl S, Dersch K, Bhakdi S, Husmann M (2006) Pore-forming staphylococcus aureus alpha-toxin triggers epidermal growth factor receptor-dependent proliferation. Cell Microbiol 8:1591–1600PubMedCrossRefGoogle Scholar
  58. 58.
    Huffman DL, Abrami L, Sasik R, Corbeil J, van der Goot FG, Aroian RV (2004) Mitogen-activated protein kinase pathways defend against bacterial pore-forming toxins. Proc Natl Acad Sci U.S.A 101:10995–11000PubMedCrossRefGoogle Scholar
  59. 59.
    *Husmann M, Dersch K, Bobkiewicz W, Beckmann E, Veerachato G, Bhakdi S (2006) Differential role of p38 mitogen activated protein kinase for cellular recovery from attack by pore-forming S. aureus alpha-toxin or streptolysin O. Biochem Biophys Res Commun 344:1128–1134PubMedCrossRefGoogle Scholar
  60. 60.
    Skals M, Jorgensen NR, Leipziger J, Praetorius HA (2009) Alpha-hemolysin from Escherichia coli uses endogenous amplification through P2X receptor activation to induce hemolysis. Proc Natl Acad Sci U.S.A 106:4030–4035PubMedCrossRefGoogle Scholar
  61. 61.
    Skals M, Leipziger J, Praetorius HA (2011) Haemolysis induced by alpha-toxin from Staphylococcus aureus requires P2X receptor activation. Pflugers Arch 462:669–679PubMedCrossRefGoogle Scholar
  62. 62.
    Garcia-Marcos M, Pochet S, Marino A, Dehaye JP (2006) P2X7 and phospholipid signalling: the search of the “missing link” in epithelial cells. Cell Signal 18:2098–2104PubMedCrossRefGoogle Scholar
  63. 63.
    Garcia-Marcos M, Perez-Andres E, Tandel S, Fontanils U, Kumps A, Kabre E, Gomez-Munoz A, Marino A, Dehaye JP, Pochet S (2006) Coupling of two pools of P2X7 receptors to distinct intracellular signaling pathways in rat submandibular gland. J Lipid Res 47:705–714PubMedCrossRefGoogle Scholar
  64. 64.
    Bianco F, Perrotta C, Novellino L, Francolini M, Riganti L, Menna E, Saglietti L, Schuchman EH, Furlan R, Clementi E et al (2009) Acid sphingomyelinase activity triggers microparticle release from glial cells. EMBO J 28:1043–1054PubMedCrossRefGoogle Scholar
  65. 65.
    *Walev I, Tappe D, Gulbins E, Bhakdi S (2000) Streptolysin O-permeabilised granulocytes shed L-selectin concomitantly with ceramide generation via neutral sphingomyelinase. J Leukoc Biol 68:865–872PubMedGoogle Scholar
  66. 66.
    Jamieson GP, Snook MB, Thurlow PJ, Wiley JS (1996) Extracellular ATP causes of loss of L-selectin from human lymphocytes via occupancy of P2Z purinocepters. J Cell Physiol 166:637–642PubMedCrossRefGoogle Scholar
  67. 67.
    Gu B, Bendall LJ, Wiley JS (1998) Adenosine triphosphate-induced shedding of CD23 and L-selectin (CD62L) from lymphocytes is mediated by the same receptor but different metalloproteases. Blood 92:946–951PubMedGoogle Scholar
  68. 68.
    Elliott JI, Surprenant A, Marelli-Berg FM, Cooper JC, Cassady-Cain RL, Wooding C, Linton K, Alexander DR, Higgins CF (2005) Membrane phosphatidylserine distribution as a non-apoptotic signalling mechanism in lymphocytes. Nat Cell Biol 7:808–816PubMedCrossRefGoogle Scholar
  69. 69.
    Sluyter R, Wiley JS (2002) Extracellular adenosine 5′-triphosphate induces a loss of CD23 from human dendritic cells via activation of P2X7 receptors. Int Immunol 14:1415–1421PubMedCrossRefGoogle Scholar
  70. 70.
    Moon H, Na HY, Chong KH, Kim TJ (2006) P2X7 receptor-dependent ATP-induced shedding of CD27 in mouse lymphocytes. Immunol Lett 102:98–105PubMedCrossRefGoogle Scholar
  71. 71.
    Orsolic N (2011) Bee venom in cancer therapy. Cancer Metastasis Rev 31:173–194Google Scholar
  72. 72.
    *Sommer A, Fries A, Cornelsen I, Speck N, Koch-Nolte F, Gimpl G, Andrae J, Bhakdi S, Reiss K (2012) Melittin modulates keratinocyte function through P2-receptor-dependent ADAM activation. J Biol Chem 287:23679–23689Google Scholar
  73. 73.
    Elssner A, Duncan M, Gavrilin M, Wewers MD (2004) A novel P2X7 receptor activator, the human cathelicidin-derived peptide LL37, induces IL-1 beta processing and release. J Immunol 172:4987–4994PubMedGoogle Scholar
  74. 74.
    Wewers MD, Sarkar A (2009) P2X(7) receptor and macrophage function. Purinergic Signal 5:189–195PubMedCrossRefGoogle Scholar
  75. 75.
    Lee CC, Sun Y, Qian S, Huang HW (2011) Transmembrane pores formed by human antimicrobial peptide LL-37. Biophys J 100:1688–1696PubMedCrossRefGoogle Scholar
  76. 76.
    Tomasinsig L, Pizzirani C, Skerlavaj B, Pellegatti P, Gulinelli S, Tossi A, Di Virgilio F, Zanetti M (2008) The human cathelicidin LL-37 modulates the activities of the P2X7 receptor in a structure-dependent manner. J Biol Chem 283:30471–30481PubMedCrossRefGoogle Scholar
  77. 77.
    Tokumaru S, Sayama K, Shirakata Y, Komatsuzawa H, Ouhara K, Hanakawa Y, Yahata Y, Dai X, Tohyama M, Nagai H et al (2005) Induction of keratinocyte migration via transactivation of the epidermal growth factor receptor by the antimicrobial peptide LL-37. J Immunol 175:4662–4668PubMedGoogle Scholar

Copyright information

© Springer-Verlag 2012

Authors and Affiliations

  1. 1.Department of DermatologyChristian-Albrecht University KielKielGermany
  2. 2.Institute of Medical Microbiology and HygieneGutenberg-University MainzMainzGermany

Personalised recommendations