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Papain-Like Proteases of Staphylococcus aureus

  • Tomasz Kantyka
  • Lindsey N. Shaw
  • Jan Potempa
Chapter
Part of the Advances in Experimental Medicine and Biology book series (AEMB, volume 712)

Abstract

Staphylococcus aureus remains one of the major humanpathogens, causing a number of diverse infections. the growing antibiotic resistance, including vancomycin and methicilin-resistant strains raises the special interest in virulence mechanism of this pathogen. among a number of extracellular virulence factors, S. aureus secretes several proteases of three catalytic classes—metallo, serine and papain-like cysteine proteases. the expression of proteolytic enzymes is strictly controlled by global regulators of virulence factors expression agr and sar and proteases take a role in a phenotype change in postlogarithmic phase of growth. the staphylococcal proteases are secreted as proenzymes and undergo activation in a cascade manner.

Staphopains, two cysteine, papain-like proteases of S. aureus are both ∼20 kDa proteins that have almost identical three-dimensional structures, despite sharing limited primary sequence identity. although staphopain a displays activity similar to cathepsins, recognising hydrophobic residues at P2 position and large charged residues at P1, staphopain B differs significantly, showing significant preference towards β-branched residues at P2 and accepting only small, neutral residues at the P1 position. there is limited data available on the virulence potential of staphopains in in vivo models. However, in vitro experiments have demonstrated a very broad activity of these enzymes, including destruction of connective tissue, disturbance of clotting and kinin systems and direct interaction with host immune cells. Staphopain genes in various staphylococci species are regularly followed by a gene encoding an extremely specific inhibitor of the respective staphopain. This pattern is conserved across species and it is believed that inhibitors (staphostatins) protect the cytoplasm of the cell from premature activation of staphopains during protein folding. Notably, production and activity of staphopains is controlled on each level, from gene expression, through presence of specific inhibitors in cytoplasm, to the cascade-like activation in extracellular environment. Since these systems are highly conserved, this points to the importance of these proteases in the survival and/or pathogenicity of S. aureus.

Keywords

Staphylococcus Aureus Cysteine Protease Extracellular Protease Pathogenic Organism Host Immune Cell 
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.

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References

  1. 1.
    Foster TJ. The Staphylococcus aureus “superbug”. J Clin Invest 2004; 114(12):1693–1696.PubMedGoogle Scholar
  2. 2.
    Ferry T, Perpoint T, Vandenesch F et al. Virulence determinants in Staphylococcus aureus and their involvement in clinical syndromes. Curr Infect Dis Rep 2005; 7(6):420–428.PubMedCrossRefGoogle Scholar
  3. 3.
    Abdelnour A, Arvidson S, Bremell T et al. The accessory gene regulator (agr) controls Staphylococcus aureus virulence in a murine arthritis model. Infect Immun 1993; 61(9):3879–3885.PubMedGoogle Scholar
  4. 4.
    Cheung AL, Eberhardt KJ, Chung E et al. Diminished virulence of a sar-/agr-mutant of Staphylococcus aureus in the rabbit model of endocarditis. J Clin Invest 1994; 94(5): 1815–1822.PubMedCrossRefGoogle Scholar
  5. 5.
    Vuong C, Gotz F, Otto M. Construction and characterization of an agr deletion mutant of Staphylococcus epidermidis. Infect Immun 2000; 68(3): 1048–1053.PubMedCrossRefGoogle Scholar
  6. 6.
    Kavanaugh JS, Thoendel M, Horswill AR. A role for type I signal peptidase in Staphylococcus aureus quorum sensing. Mol Microbiol 2007; 65(3):780–798.PubMedCrossRefGoogle Scholar
  7. 7.
    Queck SY, Jameson-Lee M, Villaruz AE et al. RNAIII-independent target gene control by the agr quorum-sensing system: insight into the evolution of virulence regulation in Staphylococcus aureus. Mol Cell 2008; 32(1): 150–158.PubMedCrossRefGoogle Scholar
  8. 8.
    Novick RP. Autoinduction and signal transduction in the regulation of staphylococcal virulence. Mol Microbiol 2003; 48(6):1429–1449.PubMedCrossRefGoogle Scholar
  9. 9.
    McGavin MJ, Zahradka C, Rice K et al. Modification of the Staphylococcus aureus fibronectin binding phenotype by V8 protease. Infect Immun 1997; 65(7):2621–2628.PubMedGoogle Scholar
  10. 10.
    Karlsson A, Saravia-Otten P, Tegmark K et al. 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 2001; 69(8):4742–4748.PubMedCrossRefGoogle Scholar
  11. 11.
    McAleese FM, Walsh EJ, Sieprawska M et al. Loss of clumping factor B fibrinogen binding activity by Staphylococcus aureus involves cessation of transcription, shedding and cleavage by metalloprotease. J Biol Chem 2001; 276(32):29969–29978.PubMedCrossRefGoogle Scholar
  12. 12.
    Cheung AL, Ying P. Regulation of alpha-and beta-hemolysins by the sar locus of Staphylococcus aureus. J Bacteriol 1994; 176(3):580–585.PubMedGoogle Scholar
  13. 13.
    Chien Y, Manna AC, Projan SJ et al. SarA, a global regulator of virulence determinants in Staphylococcus aureus, binds to a conserved motif essential for sar-dependent gene regulation. J Biol Chem 1999; 274(52):37169–37176.PubMedCrossRefGoogle Scholar
  14. 14.
    Rechtin TM, Gillaspy AF, Schumacher MA et al. Characterization of the SarA virulence gene regulator of Staphylococcus aureus. Mol Microbiol 1999; 33(2):307–316.PubMedCrossRefGoogle Scholar
  15. 15.
    Novick RP, Ross HF, Projan SJ et al. Synthesis of staphylococcal virulence factors is controlled by a regulatory RNA molecule. EMBO J 1993; 12(10):3967–3975.PubMedGoogle Scholar
  16. 16.
    Chan PF, Foster SJ. Role of SarA in virulence determinant production and environmental signal transduction in Staphylococcus aureus. J Bacteriol 1998; 180(23):6232–6241.PubMedGoogle Scholar
  17. 17.
    Arvidson S. Extracellular Enzymes. In: Fischetti VA, Novick RP, Ferretti JJ, Potrnoy DA, Rood JIe, editors. Gram-positive pathogens. Washington D.C.: American Society for Microbiology, 2000: 379–385.Google Scholar
  18. 18.
    Ziebandt AK, Weber H, Rudolph J et al. Extracellular proteins of Staphylococcus aureus and the role of SarA and sigma B. Proteomics 2001; 1(4):480–493.PubMedCrossRefGoogle Scholar
  19. 19.
    Massimi I, Park E, Rice K et al. Identification of a novel maturation mechanism and restricted substrate specificity for the SspB cysteine protease of Staphylococcus aureus. J Biol Chem 2002; 277(44):41770–41777.PubMedCrossRefGoogle Scholar
  20. 20.
    Drapeau GR, Boily Y, Houmard J. Purification and properties of an extracellular protease of Staphylococcus aureus. J Biol Chem 1972; 247(20):6720–6726.PubMedGoogle Scholar
  21. 21.
    Arvidson S, Holme T, Lindholm B. Studies on extracellular proteolytic enzymes from Staphylococcus aureus. I. Purification and characterization of one neutral and one alkaline protease. Biochim Biophys Acta 1973; 302(1): 135–148.PubMedGoogle Scholar
  22. 22.
    Arvidson S. Studies on extracellular proteolytic enzymes from Staphylococcus aureus. II Isolation and characterization of an EDTA-sensitive protease. Biochim Biophys Acta 1973; 302(1):149–157.PubMedGoogle Scholar
  23. 23.
    Reed SB, Wesson CA, Liou LE et al. Molecular characterization of a novel Staphylococcus aureus serine protease operon. Infect Immun 2001; 69(3): 1521–1527.PubMedCrossRefGoogle Scholar
  24. 24.
    Rice K, Peralta R, Bast D et al. Description of staphylococcus serine protease (ssp) operon in Staphylococcus aureus and nonpolar inactivation of sspA-encoded serine protease. Infect Immun 2001; 69(1): 159–169.PubMedCrossRefGoogle Scholar
  25. 25.
    Potempa J, Watorek W, Travis J. The inactivation of human plasma alpha 1-proteinase inhibitor by proteinases from Staphylococcus aureus. J Biol Chem 1986; 261(30): 14330–14334.PubMedGoogle Scholar
  26. 26.
    Potempa J, Fedak D, Dubin A et al. Proteolytic inactivation of alpha-1-anti-chymotrypsin. Sites of cleavage and generation of chemotactic activity. J Biol Chem 1991; 266(32):21482–21487.PubMedGoogle Scholar
  27. 27.
    Prokesova L, Potuznikova B, Potempa J et al. Cleavage of human immunoglobulins by proteinase from Staphylococcus aureus. Adv Exp Med Biol 1995; 371A:613–616.PubMedGoogle Scholar
  28. 28.
    Potempa J, Banbula A, Travis J. Role of bacterial proteinases in matrix destruction and modulation of host responses. Periodontol 2000; 24:153–192.CrossRefGoogle Scholar
  29. 29.
    Imamura T, Tanase S, Szmyd G et al. Induction of vascular leakage through release of bradykinin and a novel kinin by cysteine proteinases from Staphylococcus aureus. J Exp Med 2005; 201(10):1669–1676.PubMedCrossRefGoogle Scholar
  30. 30.
    Smagur J, Guzik K, Bzowska M et al. Staphylococcal cysteine protease staphopain B (SspB) induces rapid engulfment of human neutrophils and monocytes by macrophages. Biol Chem 2009; 390(4):361–371.PubMedCrossRefGoogle Scholar
  31. 31.
    Maeda H, Yamamoto T. Pathogenic mechanisms induced by microbial proteases in microbial infections. Biol Chem Hoppe Seyler 1996; 377(4):217–226.PubMedCrossRefGoogle Scholar
  32. 32.
    Lindsay JA, Foster SJ. Interactive regulatory pathways control virulence determinant production and stability in response to environmental conditions in Staphylococcus aureus. Mol Gen Genet 1999; 262(2):323–331.PubMedCrossRefGoogle Scholar
  33. 33.
    Dunman PM, Murphy E, Haney S et al. Transcription profiling-based identification of Staphylococcus aureus genes regulated by the agr and/or sarA loci. J Bacteriol 2001; 183(24):7341–7353.PubMedCrossRefGoogle Scholar
  34. 34.
    Shaw L, Golonka E, Potempa J et al. The role and regulation of the extracellular proteases of Staphylococcus aureus. Microbiology 2004; 150(Pt 1):217–228.PubMedCrossRefGoogle Scholar
  35. 35.
    Tegmark K, Morfeldt E, Arvidson S. Regulation of agr-dependent virulence genes in Staphylococcus aureus by RNAIII from coagulase-negative staphylococci. J Bacteriol 1998; 180(12):3181–3186.PubMedGoogle Scholar
  36. 36.
    Drapeau GR. Role of metalloprotease in activation of the precursor of staphylococcal protease. J Bacteriol 1978; 136(2):607–613.PubMedGoogle Scholar
  37. 37.
    Filipek R, Rzychon M, Oleksy A et al. The Staphostatin-staphopain complex: a forward binding inhibitor in complex with its target cysteine protease. J Biol Chem 2003; 278(42):40959–40966.PubMedCrossRefGoogle Scholar
  38. 38.
    Rzychon M, Sabat A, Kosowska K et al. Staphostatins: an expanding new group of proteinase inhibitors with a unique specificity for the regulation of staphopains, Staphylococcus spp. cysteine proteinases. Mol Microbiol 2003; 49(4): 1051–1066.PubMedCrossRefGoogle Scholar
  39. 39.
    Karlsson A, Arvidson S. Variation in extracellular protease production among clinical isolates of Staphylococcus aureus due to different levels of expression of the protease repressor sarA. Infect Immun 2002; 70(8):4239–4246.PubMedCrossRefGoogle Scholar
  40. 40.
    Dubin G, Krajewski M, Popowicz G et al. A novel class of cysteine protease inhibitors: solution structure of staphostatin a from Staphylococcus aureus. Biochemistry 2003; 42(46): 13449–13456.PubMedCrossRefGoogle Scholar
  41. 41.
    Rzychon M, Filipek R, Sabat A et al. Staphostatins resemble lipocalins, not cystatins in fold. Protein Sci 2003; 12(10):2252–2256.PubMedCrossRefGoogle Scholar
  42. 42.
    Nickerson NN, Joag V, McGavin MJ. Rapid autocatalytic activation of the M4 metalloprotease aureolysin is controlled by a conserved N-terminal fungalysin-thermolysin-propeptide domain. Mol Microbiol 2008; 69(6): 1530–1543.PubMedCrossRefGoogle Scholar
  43. 43.
    Marie-Claire C, Roques BP, Beaumont A. Intramolecular processing of prothermolysin. J Biol Chem 1998;273(10):5697–5701.PubMedCrossRefGoogle Scholar
  44. 44.
    Hoffman B, Schomburg D, Hecht HJ. Crystal structure of a thiol proteinase from Staphylococcus aureus V8 in the E-64 inhibitor complex. Acta Crystallographica 1993;(49):102.Google Scholar
  45. 45.
    Nickerson N, Ip J, Passos DT et al. 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 2010; 75(1): 161–177.CrossRefGoogle Scholar
  46. 46.
    Coulter SN, Schwan WR, Ng EY et al. Staphylococcus aureus genetic loci impacting growth and survival in multiple infection environments. Mol Microbiol 1998; 30(2):393–404.PubMedCrossRefGoogle Scholar
  47. 47.
    Potempa J, Pike RN. Bacterial peptidases. Contrib Microbiol 2005; 12:132–180.PubMedCrossRefGoogle Scholar
  48. 48.
    Potempa J, Dubin A, Korzus G et al. Degradation of elastin by a cysteine proteinase from Staphylococcus aureus. J Biol Chem 1988; 263(6):2664–2667.PubMedGoogle Scholar
  49. 49.
    Dubin G. Extracellular proteases of Staphylococcus spp. Biol Chem 2002; 383(7-8):1075–1086.PubMedCrossRefGoogle Scholar
  50. 50.
    Wegrzynowicz Z, Heczko PB, Drapeau GR et al. Prothrombin activation by a metalloprotease from Staphylococcus aureus. J Clin Microbiol 1980; 12(2): 138–139.PubMedGoogle Scholar
  51. 51.
    Jones RC, Deck J, Edmondson RD et al. Relative quantitative comparisons of the extracellular protein profiles of Staphylococcus aureus UAMS-1 and its sarA, agr and sarA agr regulatory mutants using one-dimensional polyacrylamide gel electrophoresis and nanocapillary liquid chromatography coupled with tandem mass spectrometry. J Bacteriol 2008; 190(15):5265–5278.PubMedCrossRefGoogle Scholar
  52. 52.
    Wladyka B, Puzia K, Dubin A. Efficient co-expression of a recombinant staphopain A and its inhibitor staphostatin A in Escherichia coli. Biochem J 2005; 385(Pt 1):181–187.PubMedCrossRefGoogle Scholar
  53. 53.
    Copeland A, Lucas S, Lapidus A et al. Complete sequence of chromosome of Staphylococcus aureus subsp.aureus JH9. 2007.Google Scholar
  54. 54.
    Filipek R, Potempa J, Bochtler M. A comparison of staphostatin B with standard mechanism serine protease inhibitors. J Biol Chem 2005; 280(15): 14669–14674.PubMedCrossRefGoogle Scholar
  55. 55.
    Dubin G, Wladyka B, Stec-Niemczyk J et al. The staphostatin family of cysteine protease inhibitors in the genus Staphylococcus as an example of parallel evolution of protease and inhibitor specificity. Biol Chem 2007; 388(2):227–235.PubMedCrossRefGoogle Scholar

Copyright information

© Landes Bioscience and Springer Science+Business Media, LLC 2011

Authors and Affiliations

  • Tomasz Kantyka
    • 1
  • Lindsey N. Shaw
    • 2
  • Jan Potempa
    • 1
    • 3
  1. 1.Department of Microbiology, Faculty of Biochemistry, Biophysics and BiotechnologyJagiellonian UniversityPoland
  2. 2.Department of Cell Biology, Microbiology and Molecular BiologyUniversity of South FloridaTampaUSA
  3. 3.Oral Health and Systemic Disease Research FacilityUniversity of Louisville School of DentistryLouisvilleUSA

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