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. PMID 4632563. doi:10.1016/0005-2744(73)90017-x.
  2. Saheb, S.A. (1976). "Purification et caractérisation dune protéase extracellulaire de Staphylococcus aureus inhibée par lE.D.T.A". Biochimie. 58: 793–804. PMID 823980. doi:10.1016/s0300-9084(76)80310-0.
  3. Drapeau, G.R. (1978). "Role of a metalloprotease in activation of the precursor of staphylococcal protease". J. Bacteriol. 136: 607–613. PMC 218585Freely accessible. PMID 711676.
  4. Potempa, J.; Porwit-Bohr, Z.; Travis, J. (1989). "Stabilization vs. degradation of Staphylococcus aureus' metalloproteinase". Biochim. Biophys. Acta. 993: 301–304. PMID 2512988. doi:10.1016/0304-4165(89)90181-5.
  5. 1 2 3 4 5 6 7 8 9 Potempa, Jan; Shaw, Lindsey N. (2013-01-01). Rawlings, Neil D.; Salvesen, Guy, eds. Handbook of Proteolytic Enzymes. Academic Press. pp. 563–569. ISBN 9780123822192. doi:10.1016/b978-0-12-382219-2.00114-9.
  6. Sabat, Artur J.; Wladyka, Benedykt; Kosowska-Shick, Klaudia; Grundmann, Hajo; van Dijl, Jan Maarten; Kowal, Julia; Appelbaum, Peter C.; Dubin, Adam; Hryniewicz, Waleria (2008-07-29). "Polymorphism, genetic exchange and intragenic recombination of the aureolysin gene among Staphylococcus aureus strains". BMC microbiology. 8: 129. ISSN 1471-2180. PMC 2515849Freely accessible. PMID 18664262. doi:10.1186/1471-2180-8-129.
  7. Shaw, Lindsey; Golonka, Ewa; Potempa, Jan; Foster, Simon J. (2004-01-01). "The role and regulation of the extracellular proteases of Staphylococcus aureus". Microbiology (Reading, England). 150 (Pt 1): 217–228. ISSN 1350-0872. PMID 14702415. doi:10.1099/mic.0.26634-0.
  8. Oscarsson, Jan; Tegmark-Wisell, Karin; Arvidson, Staffan (2006-10-01). "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: IJMM. 296 (6): 365–380. ISSN 1438-4221. PMID 16782403. doi:10.1016/j.ijmm.2006.02.019.
  9. 1 2 Burlak, Christopher; Hammer, Carl H.; Robinson, Mary-Ann; Whitney, Adeline R.; McGavin, Martin J.; Kreiswirth, Barry N.; Deleo, Frank R. (2007-05-01). "Global analysis of community-associated methicillin-resistant Staphylococcus aureus exoproteins reveals molecules produced in vitro and during infection". Cellular Microbiology. 9 (5): 1172–1190. ISSN 1462-5814. PMC 2064037Freely accessible. PMID 17217429. doi:10.1111/j.1462-5822.2006.00858.x.
  10. 1 2 3 4 5 6 7 Dubin, Grzegorz (2002-07-01). "Extracellular proteases of Staphylococcus spp". Biological Chemistry. 383 (7–8): 1075–1086. ISSN 1431-6730. PMID 12437090. doi:10.1515/BC.2002.116.
  11. Nickerson, Nicholas N.; Joag, Vineet; McGavin, Martin J. (2008-09-01). "Rapid autocatalytic activation of the M4 metalloprotease aureolysin is controlled by a conserved N-terminal fungalysin-thermolysin-propeptide domain". Molecular Microbiology. 69 (6): 1530–1543. ISSN 1365-2958. PMID 18673454. doi:10.1111/j.1365-2958.2008.06384.x.
  12. Nickerson, Nicholas N.; Prasad, Lata; Jacob, Latha; Delbaere, Louis T.; McGavin, Martin J. (2007-11-23). "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): 34129–34138. ISSN 0021-9258. PMID 17878159. doi:10.1074/jbc.M705672200.
  13. 1 2 Jusko, Monika; Potempa, Jan; Kantyka, Tomasz; Bielecka, Ewa; Miller, Halie K.; Kalinska, Magdalena; Dubin, Grzegorz; Garred, Peter; Shaw, Lindsey N. (2014-01-01). "Staphylococcal proteases aid in evasion of the human complement system". Journal of Innate Immunity. 6 (1): 31–46. ISSN 1662-8128. PMC 3972074Freely accessible. PMID 23838186. doi:10.1159/000351458.
  14. Kolar, Stacey L.; Ibarra, J. Antonio; Rivera, Frances E.; Mootz, Joe M.; Davenport, Jessica E.; Stevens, Stanley M.; Horswill, Alexander R.; Shaw, Lindsey N. (2013-02-01). "Extracellular proteases are key mediators of Staphylococcus aureus virulence via the global modulation of virulence-determinant stability". MicrobiologyOpen. 2 (1): 18–34. ISSN 2045-8827. PMC 3584211Freely accessible. PMID 23233325. doi:10.1002/mbo3.55.
  15. Koziel, Joanna; Potempa, Jan (2013-02-01). "Protease-armed bacteria in the skin". Cell and Tissue Research. 351 (2): 325–337. ISSN 1432-0878. PMC 3560952Freely accessible. PMID 22358849. doi:10.1007/s00441-012-1355-2.
  16. Potempa, Jan; Pike, Robert N. (2009-01-01). "Corruption of innate immunity by bacterial proteases". Journal of Innate Immunity. 1 (2): 70–87. ISSN 1662-8128. PMC 2743019Freely accessible. PMID 19756242. doi:10.1159/000181144.
  17. Kubica, Malgorzata; Guzik, Krzysztof; Koziel, Joanna; Zarebski, Miroslaw; Richter, Walter; Gajkowska, Barbara; Golda, Anna; Maciag-Gudowska, Agnieszka; Brix, Klaudia (2008-01-09). "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. ISSN 1932-6203. PMC 2169301Freely accessible. PMID 18183290. doi:10.1371/journal.pone.0001409.
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