Aureolysin

Identifiers
EC number 3.4.24.29
CAS number 39335-13-2
Databases
IntEnz IntEnz view
BRENDA BRENDA entry
ExPASy NiceZyme view
KEGG KEGG entry
MetaCyc metabolic pathway
PRIAM profile
PDB structures RCSB PDB PDBe PDBsum

Aureolysin (EC 3.4.24.29, protease III, staphylococcal metalloprotease, Staphylococcus aureus neutral proteinase) is an extracellular metalloprotease expressed by Staphylococcus aureus.[1][2][3][4][5] It was first identified as an EDTA-sensitive protease expressed by the S. aureus strain V8.

Genetics

Aureolysin is expressed from the gene aur, which exists in two allelic forms although being strongly conserved.[6]

Aureolysin is largely co-expressed with the other major proteases of S. aureus: aureolysin, staphopain A, and staphopain B. The transcription of aur, that occurs via a promoter controlled by "housekeeping" sigma factor σA, is up-regulated by accessory gene regulator agr, while it is repressed by staphylococcal accessory regulator sarA and by alternative sigma factor σB (a stress response modulator of Gram-positive bacteria). aur expression is highly expressed in post-exponential growth phase.[7] A more complex network of modulators and of environmental conditions affecting ssp expression have been suggested, however.[5][8] Up-regulation of aureolysin during phagocytosis have also been observed.[9]

The aur gene has a high prevalence in the genome of both commensal- and pathogenic-type S. aureus strains.[10]

Activation

Aureolysin is expressed as a zymogen, a pre-form of the enzyme, which is activated through autocatalytic degradation of a propeptide domain.[11] Its activity is dependent on zinc and calclium ions; it can be inhibited by EDTA.[10]

Function

Aureolysin is involved in the activation of other S. aureus proteases; it proteolytically activates the zymogen of the serine protease glutamyl endopeptidase, which in turn is the activator of staphopain B, a cysteine protease.[5][10][12]

Aureolysin cleaves different proteins among inflammatory regulators and immune components. Aureolysin can inactivate certain targets within the complement system, inhibiting all three pathways of complement activation.[13] Aureolysin cleaves and inactivates protease inhibitor α1-antichymotrypsin and partially inactivate α1-antitrypsin, de-regulating endogenous proteolytic activity. The cleavage of α1-antitrypsin generates a fragment chemotactic to neutrophils.[10] Aureolysin has also been shown to cleave the antimicrobial peptide LL-37.[5]

Aureolysin proteolytically activate pro-thrombin into thrombin, but somewhat contradictory also activates urokinase, and inactivates α2-antiplasmin and plasminogen activator inhibitor-1. It could potentially contribute to either coagulation triggered by coagulase or to fibrinolysis mediated by staphylokinase, or both.[5][10]

Aureolysin can cleave a bacterial surface proteins, including clumping factor B, and secreted proteins, i.a. phenol-soluble modulins (PSMs) and α-toxins.[10][14]

Biological significance

An immunization survey of human serum samples suggests that exposure to S. aureus glutamyl endopeptidase is common, although a correlation to any specific type of infection could not be established. The numerous targets of bacterial proteases, adding the complexity of other virulence factors and their genetic regulation, makes it difficult to attribute a specific role of the protease for the bacteria.[15][16]

Aureolysin appears to down-regulate the formation of biofilms. It also mediates cleavage of clumping factor B causing loss of binding of S. aureus to fibrinogen. By this it may act as a self-regulatory mechanism for dissemination and spreading in combination with activation of fibrinolysis, while the protease simultaneously provides protection against complement activation.[5][10] it has been demonstrated that aureolysin has impact for bacterial survival in human whole blood.[13] Aureolysin is also up-regulated upon phagocytosis and promotes intracellular survival.[5][9][17] Furthermore, it appears to provide resistance to LL-37, and inhibiting production of immunoglobulin by lymphocytes.[5]

While promoting dissemination and counteracts immune mechanisms, through inactivation of PSMs and α-toxins aureolysin it may suppress the pathogenic impact of the bacteria.[5]

References

  1. ↑ Arvidson, S. (1973). "Studies on extracellular proteolytic enzymes from Staphylococcus aureus. II. Isolation and characterization of an EDTA-sensitive protease". Biochim. Biophys. Acta. 302: 149–157. doi:10.1016/0005-2744(73)90017-x. PMID 4632563.
  2. ↑ Saheb SA (1976). "Purification and characterization of an extracellular protease from Staphylococcus aureus inhibited by EDTA". Biochimie (in French). 58 (7): 793–804. doi:10.1016/s0300-9084(76)80310-0. PMID 823980.
  3. ↑ Drapeau GR (November 1978). "Role of metalloprotease in activation of the precursor of staphylococcal protease". Journal of Bacteriology. 136 (2): 607–13. PMC 218585. PMID 711676.
  4. ↑ Potempa J, Porwit-Bobr Z, Travis J (December 1989). "Stabilization vs. degradation of Staphylococcus aureus metalloproteinase". Biochimica et Biophysica Acta. 993 (2–3): 301–4. doi:10.1016/0304-4165(89)90181-5. PMID 2512988.
  5. 1 2 3 4 5 6 7 8 9 Potempa J, Shaw LN (2013-01-01). Rawlings ND, Salvesen G, eds. Handbook of Proteolytic Enzymes. Academic Press. pp. 563–569. doi:10.1016/b978-0-12-382219-2.00114-9. ISBN 9780123822192.
  6. ↑ Sabat AJ, Wladyka B, Kosowska-Shick K, Grundmann H, van Dijl JM, Kowal J, Appelbaum PC, Dubin A, Hryniewicz W (July 2008). "Polymorphism, genetic exchange and intragenic recombination of the aureolysin gene among Staphylococcus aureus strains". BMC Microbiology. 8: 129. doi:10.1186/1471-2180-8-129. PMC 2515849. PMID 18664262.
  7. ↑ Shaw L, Golonka E, Potempa J, Foster SJ (January 2004). "The role and regulation of the extracellular proteases of Staphylococcus aureus". Microbiology. 150 (Pt 1): 217–28. doi:10.1099/mic.0.26634-0. PMID 14702415.
  8. ↑ Oscarsson J, Tegmark-Wisell K, Arvidson S (October 2006). "Coordinated and differential control of aureolysin (aur) and serine protease (sspA) transcription in Staphylococcus aureus by sarA, rot and agr (RNAIII)". International Journal of Medical Microbiology. 296 (6): 365–80. doi:10.1016/j.ijmm.2006.02.019. PMID 16782403.
  9. 1 2 Burlak C, Hammer CH, Robinson MA, Whitney AR, McGavin MJ, Kreiswirth BN, Deleo FR (May 2007). "Global analysis of community-associated methicillin-resistant Staphylococcus aureus exoproteins reveals molecules produced in vitro and during infection". Cellular Microbiology. 9 (5): 1172–90. doi:10.1111/j.1462-5822.2006.00858.x. PMC 2064037. PMID 17217429.
  10. 1 2 3 4 5 6 7 Dubin G (2002-07-01). "Extracellular proteases of Staphylococcus spp". Biological Chemistry. 383 (7–8): 1075–86. doi:10.1515/BC.2002.116. PMID 12437090.
  11. ↑ Nickerson NN, Joag V, McGavin MJ (September 2008). "Rapid autocatalytic activation of the M4 metalloprotease aureolysin is controlled by a conserved N-terminal fungalysin-thermolysin-propeptide domain". Molecular Microbiology. 69 (6): 1530–43. doi:10.1111/j.1365-2958.2008.06384.x. PMID 18673454.
  12. ↑ Nickerson NN, Prasad L, Jacob L, Delbaere LT, McGavin MJ (November 2007). "Activation of the SspA serine protease zymogen of Staphylococcus aureus proceeds through unique variations of a trypsinogen-like mechanism and is dependent on both autocatalytic and metalloprotease-specific processing". The Journal of Biological Chemistry. 282 (47): 34129–38. doi:10.1074/jbc.M705672200. PMID 17878159.
  13. 1 2 Jusko M, Potempa J, Kantyka T, Bielecka E, Miller HK, Kalinska M, Dubin G, Garred P, Shaw LN, Blom AM (2014-01-01). "Staphylococcal proteases aid in evasion of the human complement system". Journal of Innate Immunity. 6 (1): 31–46. doi:10.1159/000351458. PMC 3972074. PMID 23838186.
  14. ↑ Kolar SL, Ibarra JA, Rivera FE, Mootz JM, Davenport JE, Stevens SM, Horswill AR, Shaw LN (February 2013). "Extracellular proteases are key mediators of Staphylococcus aureus virulence via the global modulation of virulence-determinant stability". MicrobiologyOpen. 2 (1): 18–34. doi:10.1002/mbo3.55. PMC 3584211. PMID 23233325.
  15. ↑ Koziel J, Potempa J (February 2013). "Protease-armed bacteria in the skin". Cell and Tissue Research. 351 (2): 325–37. doi:10.1007/s00441-012-1355-2. PMC 3560952. PMID 22358849.
  16. ↑ Potempa J, Pike RN (2009-01-01). "Corruption of innate immunity by bacterial proteases". Journal of Innate Immunity. 1 (2): 70–87. doi:10.1159/000181144. PMC 2743019. PMID 19756242.
  17. ↑ Kubica M, Guzik K, Koziel J, Zarebski M, Richter W, Gajkowska B, Golda A, Maciag-Gudowska A, Brix K, Shaw L, Foster T, Potempa J (January 2008). "A potential new pathway for Staphylococcus aureus dissemination: the silent survival of S. aureus phagocytosed by human monocyte-derived macrophages". PLOS One. 3 (1): e1409. doi:10.1371/journal.pone.0001409. PMC 2169301. PMID 18183290.
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