Bacterial Proteases and Virulence

Part of the Subcellular Biochemistry book series (SCBI, volume 66)


Bacterial pathogens rely on proteolysis for variety of purposes during the infection process. In the cytosol, the main proteolytic players are the conserved Clp and Lon proteases that directly contribute to virulence through the timely degradation of virulence regulators and indirectly by providing tolerance to adverse conditions such as those experienced in the host. In the membrane, HtrA performs similar functions whereas the extracellular proteases, in close contact with host components, pave the way for spreading infections by degrading host matrix components or interfering with host cell signalling to short-circuit host cell processes. Common to both intra- and extracellular proteases is the tight control of their proteolytic activities. In general, substrate recognition by the intracellular proteases is highly selective which is, in part, attributed to the chaperone activity associated with the proteases either encoded within the same polypeptide or on separate subunits. In contrast, substrate recognition by extracellular proteases is less selective and therefore these enzymes are generally expressed as zymogens to prevent premature proteolytic activity that would be detrimental to the cell. These extracellular proteases are activated in complex cascades involving auto-processing and proteolytic maturation. Thus, proteolysis has been adopted by bacterial pathogens at multiple levels to ensure the success of the pathogen in contact with the human host.


Virulence Factor Extracellular Protease Yersinia Pestis Glutamyl Endopeptidase Host Cell Cytosol 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.



We would like to thank the Danish Council for Independent Research, Natural Sciences for support grant number: 272-08-0371.


  1. 1.
    Maurizi MR, Clark WP, Kim SH, Gottesman S (1990) Clp P represents a unique family of serine proteases. J Biol Chem 265(21):12546–12552PubMedGoogle Scholar
  2. 2.
    Wang J, Hartling JA, Flanagan JM (1997) The structure of ClpP at 2.3 A resolution suggests a model for ATP-dependent proteolysis. Cell 91(4):447–456PubMedCrossRefGoogle Scholar
  3. 3.
    Woo KM, Chung WJ, Ha DB, Goldberg AL et al (1989) Protease Ti from Escherichia coli requires ATP hydrolysis for protein breakdown but not for hydrolysis of small peptides. J Biol Chem 264(4):2088–2091PubMedGoogle Scholar
  4. 4.
    Gur E, Ottofuelling R, Dougan DA (2013) Machines of destruction – AAA+ proteases and the adaptors that control them. In: Dougan DA (ed) Regulated proteolysis in microorganisms. Springer, Subcell Biochem 66:3–33Google Scholar
  5. 5.
    Frees D, Savijoki K, Varmanen P, Ingmer H (2007) Clp ATPases and ClpP proteolytic complexes regulate vital biological processes in low GC, Gram-positive bacteria. Mol Microbiol 63(5):1285–1295PubMedCrossRefGoogle Scholar
  6. 6.
    Kim YI, Levchenko I, Fraczkowska K, Woodruff RV et al (2001) Molecular determinants of complex formation between Clp/Hsp100 ATPases and the ClpP peptidase. Nat Struct Biol 8(3):230–233PubMedCrossRefGoogle Scholar
  7. 7.
    Butler SM, Festa RA, Pearce MJ, Darwin KH (2006) Self-compartmentalized bacterial proteases and pathogenesis. Mol Microbiol 60(3):553–562PubMedCrossRefGoogle Scholar
  8. 8.
    Frees D, Chastanet A, Qazi S, Sorensen K et al (2004) Clp ATPases are required for stress tolerance, intracellular replication and biofilm formation in Staphylococcus aureus. Mol Microbiol 54(5):1445–1462PubMedCrossRefGoogle Scholar
  9. 9.
    Molière N, Turgay K (2013) General and regulatory proteolysis in Bacillus subtilis. In: Dougan DA (ed) Regulated proteolysis in microorganisms. Springer, Subcell Biochem 66:3–33Google Scholar
  10. 10.
    Frees D, Qazi SN, Hill PJ, Ingmer H (2003) Alternative roles of ClpX and ClpP in Staphylococcus aureus stress tolerance and virulence. Mol Microbiol 48(6):1565–1578PubMedCrossRefGoogle Scholar
  11. 11.
    Michel A, Agerer F, Hauck CR, Herrmann M et al (2006) Global regulatory impact of ClpP protease of Staphylococcus aureus on regulons involved in virulence, oxidative stress response, autolysis, and DNA repair. J Bacteriol 188(16):5783–5796PubMedCrossRefGoogle Scholar
  12. 12.
    Bottcher T, Sieber SA (2008) Beta-lactones as specific inhibitors of ClpP attenuate the production of extracellular virulence factors of Staphylococcus aureus. J Am Chem Soc 130(44):14400–14401PubMedCrossRefGoogle Scholar
  13. 13.
    Jelsbak L, Ingmer H, Valihrach L, Cohn MT et al (2010) The chaperone ClpX stimulates expression of Staphylococcus aureus protein A by Rot dependent and independent pathways. PLoS One 5(9):e12752PubMedCrossRefGoogle Scholar
  14. 14.
    Gaillot O, Pellegrini E, Bregenholt S, Nair S et al (2000) The ClpP serine protease is essential for the intracellular parasitism and virulence of Listeria monocytogenes. Mol Microbiol 35(6):1286–1294PubMedCrossRefGoogle Scholar
  15. 15.
    Gaillot O, Bregenholt S, Jaubert F, Di Santo JP et al (2001) Stress-induced ClpP serine protease of Listeria monocytogenes is essential for induction of listeriolysin O-dependent protective immunity. Infect Immun 69(8):4938–4943PubMedCrossRefGoogle Scholar
  16. 16.
    Nair S, Milohanic E, Berche P (2000) ClpC ATPase is required for cell adhesion and invasion of Listeria monocytogenes. Infect Immun 68(12):7061–7068PubMedCrossRefGoogle Scholar
  17. 17.
    Borezee E, Pellegrini E, Beretti JL, Berche P (2001) SvpA, a novel surface virulence-associated protein required for intracellular survival of Listeria monocytogenes. Microbiology 147(Pt 11):2913–2923PubMedGoogle Scholar
  18. 18.
    Robertson GT, Ng WL, Foley J, Gilmour R et al (2002) Global transcriptional analysis of clpP mutations of type 2 Streptococcus pneumoniae and their effects on physiology and virulence. J Bacteriol 184(13):3508–3520PubMedCrossRefGoogle Scholar
  19. 19.
    Kwon HY, Ogunniyi AD, Choi MH, Pyo SN et al (2004) The ClpP protease of Streptococcus pneumoniae modulates virulence gene expression and protects against fatal pneumococcal challenge. Infect Immun 72(10):5646–5653PubMedCrossRefGoogle Scholar
  20. 20.
    Ibrahim YM, Kerr AR, Silva NA, Mitchell TJ (2005) Contribution of the ATP-dependent protease ClpCP to the autolysis and virulence of Streptococcus pneumoniae. Infect Immun 73(2):730–740PubMedCrossRefGoogle Scholar
  21. 21.
    Webb C, Moreno M, Wilmes-Riesenberg M, Curtiss R 3rd et al (1999) Effects of DksA and ClpP protease on sigma S production and virulence in Salmonella typhimurium. Mol Microbiol 34(1):112–123PubMedCrossRefGoogle Scholar
  22. 22.
    Yamamoto T, Sashinami H, Takaya A, Tomoyasu T et al (2001) Disruption of the genes for ClpXP protease in Salmonella enterica serovar Typhimurium results in persistent infection in mice, and development of persistence requires endogenous gamma interferon and tumor necrosis factor alpha. Infect Immun 69(5):3164–3174PubMedCrossRefGoogle Scholar
  23. 23.
    Thomsen LE, Olsen JE, Foster JW, Ingmer H (2002) ClpP is involved in the stress response and degradation of misfolded proteins in Salmonella enterica serovar Typhimurium. Microbiology 148(Pt 9):2727–2733PubMedGoogle Scholar
  24. 24.
    Fang FC, Libby SJ, Buchmeier NA, Loewen PC et al (1992) The alternative sigma factor katF (rpoS) regulates Salmonella virulence. Proc Natl Acad Sci U S A 89(24):11978–11982PubMedCrossRefGoogle Scholar
  25. 25.
    Micevski D, Dougan DA (2013) Proteolytic regulation of stress response pathways in Escherichia coli. In: Dougan DA (ed) Regulated proteolysis in microorganisms. Springer, Subcell Biochem 66:105–128Google Scholar
  26. 26.
    Zhou D, Galan J (2001) Salmonella entry into host cells: the work in concert of type III secreted effector proteins. Microbes Infect 3(14–15):1293–1298PubMedCrossRefGoogle Scholar
  27. 27.
    Ramos HC, Rumbo M, Sirard JC (2004) Bacterial flagellins: mediators of pathogenicity and host immune responses in mucosa. Trends Microbiol 12(11):509–517PubMedCrossRefGoogle Scholar
  28. 28.
    Tomoyasu T, Ohkishi T, Ukyo Y, Tokumitsu A et al (2002) The ClpXP ATP-dependent protease regulates flagellum synthesis in Salmonella enterica serovar typhimurium. J Bacteriol 184(3):645–653PubMedCrossRefGoogle Scholar
  29. 29.
    Tomoyasu T, Takaya A, Isogai E, Yamamoto T (2003) Turnover of FlhD and FlhC, master regulator proteins for Salmonella flagellum biogenesis, by the ATP-dependent ClpXP protease. Mol Microbiol 48(2):443–452PubMedCrossRefGoogle Scholar
  30. 30.
    Lucas RL, Lostroh CP, DiRusso CC, Spector MP et al (2000) Multiple factors independently regulate hilA and invasion gene expression in Salmonella enterica serovar typhimurium. J Bacteriol 182(7):1872–1882PubMedCrossRefGoogle Scholar
  31. 31.
    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(7):2470–2478PubMedCrossRefGoogle Scholar
  32. 32.
    Takaya A, Suzuki M, Matsui H, Tomoyasu T et al (2003) Lon, a stress-induced ATP-dependent protease, is critically important for systemic Salmonella enterica serovar typhimurium infection of mice. Infect Immun 71(2):690–696PubMedCrossRefGoogle Scholar
  33. 33.
    Iyoda S, Watanabe H (2005) ClpXP protease controls expression of the type III protein secretion system through regulation of RpoS and GrlR levels in enterohemorrhagic Escherichia coli. J Bacteriol 187(12):4086–4094PubMedCrossRefGoogle Scholar
  34. 34.
    Brotz-Oesterhelt H, Beyer D, Kroll HP, Endermann R et al (2005) Dysregulation of bacterial proteolytic machinery by a new class of antibiotics. Nat Med 11(10):1082–1087PubMedCrossRefGoogle Scholar
  35. 35.
    Hinzen B, Raddatz S, Paulsen H, Lampe T et al (2006) Medicinal chemistry optimization of acyldepsipeptides of the enopeptin class antibiotics. ChemMedChem 1(7):689–693PubMedCrossRefGoogle Scholar
  36. 36.
    Kirstein J, Hoffmann A, Lilie H, Schmidt R et al (2009) The antibiotic ADEP reprogrammes ClpP, switching it from a regulated to an uncontrolled protease. EMBO Mol Med 1(1):37–49PubMedCrossRefGoogle Scholar
  37. 37.
    Sass P, Josten M, Famulla K, Schiffer G et al (2011) Antibiotic acyldepsipeptides activate ClpP peptidase to degrade the cell division protein FtsZ. Proc Natl Acad Sci U S A 108(42):17474–17479PubMedCrossRefGoogle Scholar
  38. 38.
    Lee BG, Park EY, Lee KE, Jeon H et al (2010) Structures of ClpP in complex with acyldepsipeptide antibiotics reveal its activation mechanism. Nat Struct Mol Biol 17(4):471–478PubMedCrossRefGoogle Scholar
  39. 39.
    Li DH, Chung YS, Gloyd M, Joseph E et al (2010) Acyldepsipeptide antibiotics induce the formation of a structured axial channel in ClpP: a model for the ClpX/ClpA-bound state of ClpP. Chem Biol 17(9):959–969PubMedCrossRefGoogle Scholar
  40. 40.
    Gominet M, Seghezzi N, Mazodier P (2011) Acyl depsipeptide (ADEP) resistance in Streptomyces. Microbiology 157(Pt 8):2226–2234PubMedCrossRefGoogle Scholar
  41. 41.
    Schmitt EK, Riwanto M, Sambandamurthy V, Roggo S et al (2011) The natural product cyclomarin kills Mycobacterium tuberculosis by targeting the ClpC1 subunit of the caseinolytic protease. Angew Chem Int Ed Engl 50(26):5889–5891PubMedCrossRefGoogle Scholar
  42. 42.
    Morsczeck C, Prokhorova T, Sigh J, Pfeiffer M et al (2008) Streptococcus pneumoniae: proteomics of surface proteins for vaccine development. Clin Microbiol Infect 14(1):74–81PubMedCrossRefGoogle Scholar
  43. 43.
    Cao J, Li D, Gong Y, Yin N et al (2009) Caseinolytic protease: a protein vaccine which could elicit serotype-independent protection against invasive pneumococcal infection. Clin Exp Immunol 156(1):52–60PubMedCrossRefGoogle Scholar
  44. 44.
    Wu K, Zhang X, Shi J, Li N et al (2010) Immunization with a combination of three pneumococcal proteins confers additive and broad protection against Streptococcus pneumoniae Infections in mice. Infect Immun 78(3):1276–1283PubMedCrossRefGoogle Scholar
  45. 45.
    Matsui H, Suzuki M, Isshiki Y, Kodama C et al (2003) Oral immunization with ATP-dependent protease-deficient mutants protects mice against subsequent oral challenge with virulent Salmonella enterica serovar typhimurium. Infect Immun 71(1):30–39PubMedCrossRefGoogle Scholar
  46. 46.
    Splichal I, Rychlik I, Gregorova D, Sebkova A et al (2007) Susceptibility of germ-free pigs to challenge with protease mutants of Salmonella enterica serovar Typhimurium. Immunobiology 212(7):577–582PubMedCrossRefGoogle Scholar
  47. 47.
    Rotanova TV, Botos I, Melnikov EE, Rasulova F et al (2006) Slicing a protease: structural features of the ATP-dependent Lon proteases gleaned from investigations of isolated domains. Protein Sci 15(8):1815–1828PubMedCrossRefGoogle Scholar
  48. 48.
    Cha SS, An YJ, Lee CR, Lee HS et al (2010) Crystal structure of Lon protease: molecular architecture of gated entry to a sequestered degradation chamber. EMBO J 29(20):3520–3530PubMedCrossRefGoogle Scholar
  49. 49.
    Tsilibaris V, Maenhaut-Michel G, Van Melderen L (2006) Biological roles of the Lon ATP-dependent protease. Res Microbiol 157(8):701–713PubMedCrossRefGoogle Scholar
  50. 50.
    Takaya A, Kubota Y, Isogai E, Yamamoto T (2005) Degradation of the HilC and HilD regulator proteins by ATP-dependent Lon protease leads to downregulation of Salmonella pathogenicity island 1 gene expression. Mol Microbiol 55(3):839–852PubMedCrossRefGoogle Scholar
  51. 51.
    Gur E, Sauer RT (2008) Recognition of misfolded proteins by Lon, a AAA(+) protease. Genes Dev 22(16):2267–2277PubMedCrossRefGoogle Scholar
  52. 52.
    Gur E (2013) The Lon AAA+ protease. In: Dougan DA (ed) Regulated proteolysis in microorganisms. Springer, Subcell Biochem 66:35–51Google Scholar
  53. 53.
    Boddicker JD, Jones BD (2004) Lon protease activity causes down-regulation of Salmonella pathogenicity island 1 invasion gene expression after infection of epithelial cells. Infect Immun 72(4):2002–2013PubMedCrossRefGoogle Scholar
  54. 54.
    Takaya A, Tomoyasu T, Tokumitsu A, Morioka M et al (2002) The ATP-dependent lon protease of Salmonella enterica serovar Typhimurium regulates invasion and expression of genes carried on Salmonella pathogenicity island 1. J Bacteriol 184(1):224–232PubMedCrossRefGoogle Scholar
  55. 55.
    Schechter LM, Lee CA (2001) AraC/XylS family members, HilC and HilD, directly bind and derepress the Salmonella typhimurium hilA promoter. Mol Microbiol 40(6):1289–1299PubMedCrossRefGoogle Scholar
  56. 56.
    Jackson MW, Silva-Herzog E, Plano GV (2004) The ATP-dependent ClpXP and Lon proteases regulate expression of the Yersinia pestis type III secretion system via regulated proteolysis of YmoA, a small histone-like protein. Mol Microbiol 54(5):1364–1378PubMedCrossRefGoogle Scholar
  57. 57.
    Herbst K, Bujara M, Heroven AK, Opitz W et al (2009) Intrinsic thermal sensing controls proteolysis of Yersinia virulence regulator RovA. PLoS Pathog 5(5):e1000435PubMedCrossRefGoogle Scholar
  58. 58.
    Takaya A, Tabuchi F, Tsuchiya H, Isogai E et al (2008) Negative regulation of quorum-sensing systems in Pseudomonas aeruginosa by ATP-dependent Lon protease. J Bacteriol 190(12):4181–4188PubMedCrossRefGoogle Scholar
  59. 59.
    Bertani I, Rampioni G, Leoni L, Venturi V (2007) The Pseudomonas putida Lon protease is involved in N-acyl homoserine lactone quorum sensing regulation. BMC Microbiol 7:71PubMedCrossRefGoogle Scholar
  60. 60.
    Lipinska B, Fayet O, Baird L, Georgopoulos C (1989) Identification, characterization, and mapping of the Escherichia coli htrA gene, whose product is essential for bacterial growth only at elevated temperatures. J Bacteriol 171(3):1574–1584PubMedGoogle Scholar
  61. 61.
    Rosch JW, Caparon MG (2005) The ExPortal: an organelle dedicated to the biogenesis of secreted proteins in Streptococcus pyogenes. Mol Microbiol 58(4):959–968PubMedCrossRefGoogle Scholar
  62. 62.
    Lipinska B, Zylicz M, Georgopoulos C (1990) The HtrA (DegP) protein, essential for Escherichia coli survival at high temperatures, is an endopeptidase. J Bacteriol 172(4):1791–1797PubMedGoogle Scholar
  63. 63.
    Krojer T, Garrido-Franco M, Huber R, Ehrmann M et al (2002) Crystal structure of DegP (HtrA) reveals a new protease-chaperone machine. Nature 416(6879):455–459PubMedCrossRefGoogle Scholar
  64. 64.
    Spiess C, Beil A, Ehrmann M (1999) A temperature-dependent switch from chaperone to protease in a widely conserved heat shock protein. Cell 97(3):339–347PubMedCrossRefGoogle Scholar
  65. 65.
    Krojer T, Sawa J, Schafer E, Saibil HR et al (2008) Structural basis for the regulated protease and chaperone function of DegP. Nature 453(7197):885–890PubMedCrossRefGoogle Scholar
  66. 66.
    Clausen T, Kaiser M, Huber R, Ehrmann M (2011) HTRA proteases: regulated proteolysis in protein quality control. Nat Rev Mol Cell Biol 12(3):152–162PubMedCrossRefGoogle Scholar
  67. 67.
    Krojer T, Pangerl K, Kurt J, Sawa J et al (2008) Interplay of PDZ and protease domain of DegP ensures efficient elimination of misfolded proteins. Proc Natl Acad Sci U S A 105(22):7702–7707PubMedCrossRefGoogle Scholar
  68. 68.
    Subrini O, Betton JM (2009) Assemblies of DegP underlie its dual chaperone and protease function. FEMS Microbiol Lett 296(2):143–148PubMedCrossRefGoogle Scholar
  69. 69.
    Johnson K, Charles I, Dougan G, Pickard D et al (1991) The role of a stress-response protein in Salmonella typhimurium virulence. Mol Microbiol 5(2):401–407PubMedCrossRefGoogle Scholar
  70. 70.
    Humphreys S, Stevenson A, Bacon A, Weinhardt AB et al (1999) The alternative sigma factor, sigmaE, is critically important for the virulence of Salmonella typhimurium. Infect Immun 67(4):1560–1568PubMedGoogle Scholar
  71. 71.
    Baumler AJ, Kusters JG, Stojiljkovic I, Heffron F (1994) Salmonella typhimurium loci involved in survival within macrophages. Infect Immun 62(5):1623–1630PubMedGoogle Scholar
  72. 72.
    Elzer PH, Phillips RW, Kovach ME, Peterson KM et al (1994) Characterization and genetic complementation of a Brucella abortus high-temperature-requirement A (htrA) deletion mutant. Infect Immun 62(10):4135–4139PubMedGoogle Scholar
  73. 73.
    Yamamoto T, Hanawa T, Ogata S, Kamiya S (1996) Identification and characterization of the Yersinia enterocolitica gsrA gene, which protectively responds to intracellular stress induced by macrophage phagocytosis and to extracellular environmental stress. Infect Immun 64(8):2980–2987PubMedGoogle Scholar
  74. 74.
    Lewis C, Skovierova H, Rowley G, Rezuchova B et al (2009) Salmonella enterica Serovar Typhimurium HtrA: regulation of expression and role of the chaperone and protease activities during infection. Microbiology 155(Pt 3):873–881PubMedCrossRefGoogle Scholar
  75. 75.
    Brondsted L, Andersen MT, Parker M, Jorgensen K et al (2005) The HtrA protease of Campylobacter jejuni is required for heat and oxygen tolerance and for optimal interaction with human epithelial cells. Appl Environ Microbiol 71(6):3205–3212PubMedCrossRefGoogle Scholar
  76. 76.
    Novik V, Hofreuter D, Galan JE (2010) Identification of Campylobacter jejuni genes involved in its interaction with epithelial cells. Infect Immun 78(8):3540–3553PubMedCrossRefGoogle Scholar
  77. 77.
    Champion OL, Karlyshev AV, Senior NJ, Woodward M et al (2010) Insect infection model for Campylobacter jejuni reveals that O-methyl phosphoramidate has insecticidal activity. J Infect Dis 201(5):776–782PubMedGoogle Scholar
  78. 78.
    Baek KT, Vegge CS, Brondsted L (2011) HtrA chaperone activity contributes to host cell binding in Campylobacter jejuni. Gut Pathog 3:13PubMedCrossRefGoogle Scholar
  79. 79.
    Baek KT, Vegge CS, Skorko-Glonek J, Brondsted L (2011) Different contributions of HtrA protease and chaperone activities to Campylobacter jejuni stress tolerance and physiology. Appl Environ Microbiol 77(1):57–66PubMedCrossRefGoogle Scholar
  80. 80.
    Jong WS, ten Hagen-Jongman CM, Ruijter E, Orru RV et al (2010) YidC is involved in the biogenesis of the secreted autotransporter hemoglobin protease. J Biol Chem 285(51):39682–39690PubMedCrossRefGoogle Scholar
  81. 81.
    Bodelon G, Marin E, Fernandez LA (2009) Role of periplasmic chaperones and BamA (YaeT/Omp85) in folding and secretion of intimin from enteropathogenic Escherichia coli strains. J Bacteriol 191(16):5169–5179PubMedCrossRefGoogle Scholar
  82. 82.
    Ruiz-Perez F, Henderson IR, Leyton DL, Rossiter AE et al (2009) Roles of periplasmic chaperone proteins in the biogenesis of serine protease autotransporters of Enterobacteriaceae. J Bacteriol 191(21):6571–6583PubMedCrossRefGoogle Scholar
  83. 83.
    Humphries RM, Griener TP, Vogt SL, Mulvey GL et al (2010) N-acetyllactosamine-induced retraction of bundle-forming pili regulates virulence-associated gene expression in enteropathogenic Escherichia coli. Mol Microbiol 76(5):1111–1126PubMedCrossRefGoogle Scholar
  84. 84.
    Vogt SL, Nevesinjac AZ, Humphries RM, Donnenberg MS et al (2010) The Cpx envelope stress response both facilitates and inhibits elaboration of the enteropathogenic Escherichia coli bundle-forming pilus. Mol Microbiol 76(5):1095–1110PubMedCrossRefGoogle Scholar
  85. 85.
    Baud C, Gutsche I, Willery E, de Paepe D et al (2011) Membrane-associated DegP in Bordetella chaperones a repeat-rich secretory protein. Mol Microbiol 80(6):1625–1636PubMedCrossRefGoogle Scholar
  86. 86.
    Baud C, Hodak H, Willery E, Drobecq H et al (2009) Role of DegP for two-partner secretion in Bordetella. Mol Microbiol 74(2):315–329PubMedCrossRefGoogle Scholar
  87. 87.
    Purdy GE, Fisher CR, Payne SM (2007) IcsA surface presentation in Shigella flexneri requires the periplasmic chaperones DegP, Skp, and SurA. J Bacteriol 189(15):5566–5573PubMedCrossRefGoogle Scholar
  88. 88.
    Purdy GE, Hong M, Payne SM (2002) Shigella flexneri DegP facilitates IcsA surface expression and is required for efficient intercellular spread. Infect Immun 70(11):6355–6364PubMedCrossRefGoogle Scholar
  89. 89.
    Bumann D, Aksu S, Wendland M, Janek K et al (2002) Proteome analysis of secreted proteins of the gastric pathogen Helicobacter pylori. Infect Immun 70(7):3396–3403PubMedCrossRefGoogle Scholar
  90. 90.
    Lower M, Weydig C, Metzler D, Reuter A et al (2008) Prediction of extracellular proteases of the human pathogen Helicobacter pylori reveals proteolytic activity of the Hp1018/19 protein HtrA. PLoS One 3(10):e3510PubMedCrossRefGoogle Scholar
  91. 91.
    Hoy B, Lower M, Weydig C, Carra G et al (2010) Helicobacter pylori HtrA is a new secreted virulence factor that cleaves E-cadherin to disrupt intercellular adhesion. EMBO Rep 11(10):798–804PubMedCrossRefGoogle Scholar
  92. 92.
    Wu X, Lei L, Gong S, Chen D et al (2011) The chlamydial periplasmic stress response serine protease cHtrA is secreted into host cell cytosol. BMC Microbiol 11:87PubMedCrossRefGoogle Scholar
  93. 93.
    Cole JN, Aquilina JA, Hains PG, Henningham A et al (2007) Role of group A Streptococcus HtrA in the maturation of SpeB protease. Proteomics 7(24):4488–4498PubMedCrossRefGoogle Scholar
  94. 94.
    Lyon WR, Caparon MG (2004) Role for serine protease HtrA (DegP) of Streptococcus pyogenes in the biogenesis of virulence factors SpeB and the hemolysin streptolysin S. Infect Immun 72(3):1618–1625PubMedCrossRefGoogle Scholar
  95. 95.
    Rigoulay C, Entenza JM, Halpern D, Widmer E et al (2005) Comparative analysis of the roles of HtrA-like surface proteases in two virulent Staphylococcus aureus strains. Infect Immun 73(1):563–572PubMedCrossRefGoogle Scholar
  96. 96.
    Biswas S, Biswas I (2005) Role of HtrA in surface protein expression and biofilm formation by Streptococcus mutans. Infect Immun 73(10):6923–6934PubMedCrossRefGoogle Scholar
  97. 97.
    Wilson RL, Brown LL, Kirkwood-Watts D, Warren TK et al (2006) Listeria monocytogenes 10403S HtrA is necessary for resistance to cellular stress and virulence. Infect Immun 74(1):765–768PubMedCrossRefGoogle Scholar
  98. 98.
    Chitlaru T, Zaide G, Ehrlich S, Inbar I et al (2011) HtrA is a major virulence determinant of Bacillus anthracis. Mol Microbiol 81(6):1542–1559PubMedCrossRefGoogle Scholar
  99. 99.
    Arvidson S (2006) Extracellular enzymes. In: Fischetti VA (ed) Gram-positive pathogens (2nd edn.). ASM Press.Google Scholar
  100. 100.
    Novick RP (2003) Autoinduction and signal transduction in the regulation of staphylococcal virulence. Mol Microbiol 48(6):1429–1449PubMedCrossRefGoogle Scholar
  101. 101.
    Shaw L, Golonka E, Potempa J, Foster SJ (2004) The role and regulation of the extracellular proteases of Staphylococcus aureus. Microbiology 150(Pt 1):217–228PubMedCrossRefGoogle Scholar
  102. 102.
    Drapeau GR (1978) Role of metalloprotease in activation of the precursor of staphylococcal protease. J Bacteriol 136(2):607–613PubMedGoogle Scholar
  103. 103.
    Lindsay JA, Foster SJ (1999) Interactive regulatory pathways control virulence determinant production and stability in response to environmental conditions in Staphylococcus aureus. Mol Gen Genet 262(2):323–331PubMedCrossRefGoogle Scholar
  104. 104.
    Chan PF, Foster SJ (1998) The role of environmental factors in the regulation of virulence-determinant expression in Staphylococcus aureus 8325–4. Microbiology 144(Pt 9):2469–2479PubMedCrossRefGoogle Scholar
  105. 105.
    Rice K, Peralta R, Bast D, de Azavedo J et al (2001) Description of staphylococcus serine protease (ssp) operon in Staphylococcus aureus and nonpolar inactivation of sspA-encoded serine protease. Infect Immun 69(1):159–169PubMedCrossRefGoogle Scholar
  106. 106.
    Nickerson N, Ip J, Passos DT, McGavin MJ (2010) Comparison of Staphopain A (ScpA) and B (SspB) precursor activation mechanisms reveals unique secretion kinetics of proSspB (Staphopain B), and a different interaction with its cognate Staphostatin, SspC. Mol Microbiol 75(1):161–177PubMedCrossRefGoogle Scholar
  107. 107.
    Nickerson NN, Joag V, McGavin MJ (2008) Rapid autocatalytic activation of the M4 metalloprotease aureolysin is controlled by a conserved N-terminal fungalysin-thermolysin-propeptide domain. Mol Microbiol 69(6):1530–1543PubMedCrossRefGoogle Scholar
  108. 108.
    Massimi I, Park E, Rice K, Muller-Esterl W et al (2002) Identification of a novel maturation mechanism and restricted substrate specificity for the SspB cysteine protease of Staphylococcus aureus. J Biol Chem 277(44):41770–41777PubMedCrossRefGoogle Scholar
  109. 109.
    Rzychon M, Sabat A, Kosowska K, Potempa J et al (2003) Staphostatins: an expanding new group of proteinase inhibitors with a unique specificity for the regulation of staphopains Staphylococcus spp. cysteine proteinases. Mol Microbiol 49(4):1051–1066PubMedCrossRefGoogle Scholar
  110. 110.
    Foster TJ (2005) Immune evasion by staphylococci. Nat Rev Microbiol 3(12):948–958PubMedCrossRefGoogle Scholar
  111. 111.
    Foster TJ, Hook M (1998) Surface protein adhesins of Staphylococcus aureus. Trends Microbiol 6(12):484–488PubMedCrossRefGoogle Scholar
  112. 112.
    McGavin MJ, Zahradka C, Rice K, Scott JE (1997) Modification of the Staphylococcus aureus fibronectin binding phenotype by V8 protease. Infect Immun 65(7):2621–2628PubMedGoogle Scholar
  113. 113.
    Karlsson A, Saravia-Otten P, Tegmark K, Morfeldt E et al (2001) Decreased amounts of cell wall-associated protein A and fibronectin-binding proteins in Staphylococcus aureus sarA mutants due to up-regulation of extracellular proteases. Infect Immun 69(8):4742–4748PubMedCrossRefGoogle Scholar
  114. 114.
    McAleese FM, Walsh EJ, Sieprawska M, Potempa J et al (2001) Loss of clumping factor B fibrinogen binding activity by Staphylococcus aureus involves cessation of transcription, shedding and cleavage by metalloprotease. J Biol Chem 276(32):29969–29978PubMedCrossRefGoogle Scholar
  115. 115.
    Potempa J, Dubin A, Korzus G, Travis J (1988) Degradation of elastin by a cysteine proteinase from Staphylococcus aureus. J Biol Chem 263(6):2664–2667PubMedGoogle Scholar
  116. 116.
    Ohbayashi T, Irie A, Murakami Y, Nowak M et al (2011) Degradation of fibrinogen and collagen by staphopains, cysteine proteases released from Staphylococcus aureus. Microbiology 157(Pt 3):786–792PubMedCrossRefGoogle Scholar
  117. 117.
    Mayer-Scholl A, Averhoff P, Zychlinsky A (2004) How do neutrophils and pathogens interact? Curr Opin Microbiol 7(1):62–66PubMedCrossRefGoogle Scholar
  118. 118.
    Greenberg S, Grinstein S (2002) Phagocytosis and innate immunity. Curr Opin Immunol 14(1):136–145PubMedCrossRefGoogle Scholar
  119. 119.
    Smagur J, Guzik K, Magiera L, Bzowska M et al (2009) A new pathway of staphylococcal pathogenesis: apoptosis-like death induced by Staphopain B in human neutrophils and monocytes. J Innate Immun 1(2):98–108PubMedCrossRefGoogle Scholar
  120. 120.
    Kulig P, Zabel BA, Dubin G, Allen SJ et al (2007) Staphylococcus aureus-derived staphopain B, a potent cysteine protease activator of plasma chemerin. J Immunol 178(6):3713–3720PubMedGoogle Scholar
  121. 121.
    Otto M (2008) Staphylococcal biofilms. Curr Top Microbiol Immunol 322:207–228PubMedCrossRefGoogle Scholar
  122. 122.
    Marti M, Trotonda MP, Tormo-Mas MA, Vergara-Irigaray M et al (2010) Extracellular proteases inhibit protein-dependent biofilm formation in Staphylococcus aureus. Microbes Infect 12(1):55–64PubMedCrossRefGoogle Scholar
  123. 123.
    Boles BR, Horswill AR (2008) Agr-mediated dispersal of Staphylococcus aureus biofilms. PLoS Pathog 4(4):e1000052PubMedCrossRefGoogle Scholar
  124. 124.
    Reed SB, Wesson CA, Liou LE, Trumble WR et al (2001) Molecular characterization of a novel Staphylococcus aureus serine protease operon. Infect Immun 69(3):1521–1527PubMedCrossRefGoogle Scholar
  125. 125.
    Coulter SN, Schwan WR, Ng EY, Langhorne MH et al (1998) Staphylococcus aureus genetic loci impacting growth and survival in multiple infection environments. Mol Microbiol 30(2):393–404PubMedCrossRefGoogle Scholar
  126. 126.
    Bisno AL, Stevens DL (1996) Streptococcal infections of skin and soft tissues. N Engl J Med 334(4):240–245PubMedCrossRefGoogle Scholar
  127. 127.
    Rasmussen M, Bjorck L (2002) Proteolysis and its regulation at the surface of Streptococcus pyogenes. Mol Microbiol 43(3):537–544PubMedCrossRefGoogle Scholar
  128. 128.
    Collin M, Olsen A (2001) Effect of SpeB and EndoS from Streptococcus pyogenes on human immunoglobulins. Infect Immun 69(11):7187–7189PubMedCrossRefGoogle Scholar
  129. 129.
    Collin M, Olsen A (2001) EndoS, a novel secreted protein from Streptococcus pyogenes with endoglycosidase activity on human IgG. EMBO J 20(12):3046–3055PubMedCrossRefGoogle Scholar
  130. 130.
    Collin M, Svensson MD, Sjoholm AG, Jensenius JC et al (2002) EndoS and SpeB from Streptococcus pyogenes inhibit immunoglobulin-mediated opsonophagocytosis. Infect Immun 70(12):6646–6651PubMedCrossRefGoogle Scholar
  131. 131.
    Chaussee MS, Phillips ER, Ferretti JJ (1997) Temporal production of streptococcal erythrogenic toxin B (streptococcal cysteine proteinase) in response to nutrient depletion. Infect Immun 65(5):1956–1959PubMedGoogle Scholar
  132. 132.
    von Pawel-Rammingen U, Johansson BP, Bjorck L (2002) IdeS, a novel streptococcal cysteine proteinase with unique specificity for immunoglobulin G. EMBO J 21(7):1607–1615CrossRefGoogle Scholar
  133. 133.
    von Pawel-Rammingen U, Bjorck L (2003) IdeS and SpeB: immunoglobulin-degrading cysteine proteinases of Streptococcus pyogenes. Curr Opin Microbiol 6(1):50–55CrossRefGoogle Scholar
  134. 134.
    Hidalgo-Grass C, Mishalian I, Dan-Goor M, Belotserkovsky I et al (2006) A streptococcal protease that degrades CXC chemokines and impairs bacterial clearance from infected tissues. EMBO J 25(19):4628–4637PubMedCrossRefGoogle Scholar
  135. 135.
    Sumby P, Zhang S, Whitney AR, Falugi F et al (2008) A chemokine-degrading extracellular protease made by group A Streptococcus alters pathogenesis by enhancing evasion of the innate immune response. Infect Immun 76(3):978–985PubMedCrossRefGoogle Scholar
  136. 136.
    Zinkernagel AS, Timmer AM, Pence MA, Locke JB et al (2008) The IL-8 protease SpyCEP/ScpC of group A Streptococcus promotes resistance to neutrophil killing. Cell Host Microbe 4(2):170–178PubMedCrossRefGoogle Scholar
  137. 137.
    Gryllos I, Tran-Winkler HJ, Cheng MF, Chung H et al (2008) Induction of group A Streptococcus virulence by a human antimicrobial peptide. Proc Natl Acad Sci U S A 105(43):16755–16760PubMedCrossRefGoogle Scholar
  138. 138.
    Bryan JD, Shelver DW (2009) Streptococcus agalactiae CspA is a serine protease that inactivates chemokines. J Bacteriol 191(6):1847–1854PubMedCrossRefGoogle Scholar
  139. 139.
    Bever RA, Iglewski BH (1988) Molecular characterization and nucleotide sequence of the Pseudomonas aeruginosa elastase structural gene. J Bacteriol 170(9):4309–4314PubMedGoogle Scholar
  140. 140.
    Heck LW, Morihara K, McRae WB, Miller EJ (1986) Specific cleavage of human type III and IV collagens by Pseudomonas aeruginosa elastase. Infect Immun 51(1):115–118PubMedGoogle Scholar
  141. 141.
    Castellino FJ, Ploplis VA (2005) Structure and function of the plasminogen/plasmin system. Thromb Haemost 93(4):647–654PubMedGoogle Scholar
  142. 142.
    Beaufort N, Seweryn P, de Bentzmann S, Tang A et al (2010) Activation of human pro-urokinase by unrelated proteases secreted by Pseudomonas aeruginosa. Biochem J 428(3):473–482PubMedCrossRefGoogle Scholar
  143. 143.
    Leduc D, Beaufort N, de Bentzmann S, Rousselle JC et al (2007) The Pseudomonas aeruginosa LasB metalloproteinase regulates the human urokinase-type plasminogen activator receptor through domain-specific endoproteolysis. Infect Immun 75(8):3848–3858PubMedCrossRefGoogle Scholar
  144. 144.
    Haiko J, Laakkonen L, Juuti K, Kalkkinen N et al (2010) The omptins of Yersinia pestis and Salmonella enterica cleave the reactive center loop of plasminogen activator inhibitor 1. J Bacteriol 192(18):4553–4561PubMedCrossRefGoogle Scholar
  145. 145.
    Ramu P, Lobo LA, Kukkonen M, Bjur E et al (2008) Activation of pro-matrix metalloproteinase-9 and degradation of gelatin by the surface protease PgtE of Salmonella enterica serovar Typhimurium. Int J Med Microbiol 298(3–4):263–278PubMedCrossRefGoogle Scholar
  146. 146.
    Galvan EM, Lasaro MA, Schifferli DM (2008) Capsular antigen fraction 1 and Pla modulate the susceptibility of Yersinia pestis to pulmonary antimicrobial peptides such as cathelicidin. Infect Immun 76(4):1456–1464PubMedCrossRefGoogle Scholar
  147. 147.
    Guina T, Yi EC, Wang H, Hackett M et al (2000) A PhoP-regulated outer membrane protease of Salmonella enterica serovar typhimurium promotes resistance to alpha-helical antimicrobial peptides. J Bacteriol 182(14):4077–4086PubMedCrossRefGoogle Scholar
  148. 148.
    Schmidtchen A, Frick IM, Andersson E, Tapper H et al (2002) Proteinases of common pathogenic bacteria degrade and inactivate the antibacterial peptide LL-37. Mol Microbiol 46(1):157–168PubMedCrossRefGoogle Scholar
  149. 149.
    Sieprawska-Lupa M, Mydel P, Krawczyk K, Wojcik K et al (2004) Degradation of human antimicrobial peptide LL-37 by Staphylococcus aureus-derived proteinases. Antimicrob Agents Chemother 48(12):4673–4679PubMedCrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media Dordrecht 2013

Authors and Affiliations

  1. 1.Department of Veterinary Disease Biology, Faculty of Life SciencesUniversity of CopenhagenFrederiksbergDenmark

Personalised recommendations