Staphopain A (Staphylococcus aureus)

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Staphopain A
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EC no. 3.4.22.48
CAS no. 347841-89-8
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Staphopain A (EC 3.4.22.48, ScpA, ScpAaur, staphylopain A, staphylococcal cysteine proteinase) is a secreted cysteine protease produced by Staphylococcus aureus . It was first identified in the S. aureus V8 strain as a papain-like cysteine protease. The protease distinguishes itself from the other major proteases of S. aureus in its very broad specificity and its ability to degrade elastin. [1] [2]

Contents

Genetics

Staphopain A expressed from the gene scpA within the scp operon. The operon also contains the gene scpB for staphostatin A (specific inhibitor of staphopain A), downstream of scpA. [3] [4]

Staphopain A is largely co-expressed with the other three major proteases of S. aureus: aureolysin, glutamyl endopeptidase, and staphopain B. The transcription of scp occurs via a promoter controlled by "housekeeping" sigma factor σA and up-regulated by accessory gene regulator agr. It is at also repressed by staphylococcal accessory regulator sarA and by alternative sigma factor σB (a stress response modulator of Gram-positive bacteria). ssp expression is highly expressed in post-exponential growth phase. [4] A more complex network of modulators and of environmental conditions affecting ssp expression have been suggested, however. Up-regulation of aureolysin during phagocytosis have also been observed. [5] [6]

The scpA gene has a high prevalence in the genome of both commensal- and pathogenic-type S. aureus strains. [7]

Activation & inhibition

Staphopain A is expressed as an inactive zymogen. In contrast to the other proteases, however, it appears to undergo rapid autocatalytic activation. It is thus also independent of the activation cascade of the three other proteases. [4] [8]

S. aureus expresses the intracellular inhibitor staphostatin A, specific against staphopain A. As the activation of staphopain A could occur before it has been secreted by the bacteria, the staphostatin acts as prevention against harmful intracellular activity of the protease. [3] [8] [9]

Function

Staphopain A is elastinolytic to a degree fairly equal to that of neutrophil elastase, and has a very broad specificity proteolysis. [1] [2] [10]

Staphopain A is inhibited by phosphorylated cystatin α and α2-macroglobulin. [1] [2]

Staphopain A can cleave and lower the activity α1-antitrypsin, [1] [2] and inactivate several complement system components. [11]

Biological significance

Staphopain A was shown to inhibit activation of the complement system activation by cleaving components that are part of all three pathways (the classical, alternative, and lectin pathways) of activation. It shows a duplex role in affecting chemotaxis; while inactivating neutrophil CXCR2 receptor, generates an active C5a fragment of C5 (although inactivating C5b). [11] [12] However, it has yet to prove any significant impact on the outcome of infection. Inhibition of staphopain A by phosphorylated cystatin α did prevent colony formation in skin tissue, but the effect could also be attributed to staphopain B. Mutation of scpA did not show any impact on the outcome of a skin abscess nor a septic arthritis model. [4] [13] [14] [15] Overlapping activity with the other proteases, plus the complexity of virulence determinants and the infection site environment makes it difficult to determine the impact of the protease in pathogenesis. [1] [2]

The elastinolytic properties of the protease could assist in spread of bacteria and also symptomatically to connective tissue destruction. [1] [2] [10]

Staphopain A participates in S. aureus self-regulatory events, by altering the phenotype of the bacteria via cleavage of surface proteins and by preventing biofilm formation. [1] [16]

Related Research Articles

<i>Staphylococcus aureus</i> Species of Gram-positive bacterium

Staphylococcus aureus is a Gram-positive spherically shaped bacterium, a member of the Bacillota, and is a usual member of the microbiota of the body, frequently found in the upper respiratory tract and on the skin. It is often positive for catalase and nitrate reduction and is a facultative anaerobe that can grow without the need for oxygen. Although S. aureus usually acts as a commensal of the human microbiota, it can also become an opportunistic pathogen, being a common cause of skin infections including abscesses, respiratory infections such as sinusitis, and food poisoning. Pathogenic strains often promote infections by producing virulence factors such as potent protein toxins, and the expression of a cell-surface protein that binds and inactivates antibodies. S. aureus is one of the leading pathogens for deaths associated with antimicrobial resistance and the emergence of antibiotic-resistant strains, such as methicillin-resistant S. aureus (MRSA), is a worldwide problem in clinical medicine. Despite much research and development, no vaccine for S. aureus has been approved.

<span class="mw-page-title-main">Staphylococcal enteritis</span> Medical condition

Staphylococcal enteritis is an inflammation that is usually caused by eating or drinking substances contaminated with staph enterotoxin. The toxin, not the bacterium, settles in the small intestine and causes inflammation and swelling. This in turn can cause abdominal pain, cramping, dehydration, diarrhea and fever.

Virulence factors are cellular structures, molecules and regulatory systems that enable microbial pathogens to achieve the following:

<span class="mw-page-title-main">Cathepsin S</span> Protein-coding gene in the species Homo sapiens

Cathepsin S is a protein that in humans is encoded by the CTSS gene. Transcript variants utilizing alternative polyadenylation signals exist for this gene.

<span class="mw-page-title-main">Cathepsin B</span> Protein-coding gene in the species Homo sapiens

Cathepsin B belongs to a family of lysosomal cysteine proteases known as the cysteine cathepsins and plays an important role in intracellular proteolysis. In humans, cathepsin B is encoded by the CTSB gene. Cathepsin B is upregulated in certain cancers, in pre-malignant lesions, and in various other pathological conditions.

<span class="mw-page-title-main">Hemolysin</span> Molecule destroying the membrane of red blood cells

Hemolysins or haemolysins are lipids and proteins that cause lysis of red blood cells by disrupting the cell membrane. Although the lytic activity of some microbe-derived hemolysins on red blood cells may be of great importance for nutrient acquisition, many hemolysins produced by pathogens do not cause significant destruction of red blood cells during infection. However, hemolysins are often capable of lysing red blood cells in vitro.

RNAIII is a stable 514 nt regulatory RNA transcribed by the P3 promoter of the Staphylococcus aureus quorum-sensing agr system ). It is the major effector of the agr regulon, which controls the expression of many S. aureus genes encoding exoproteins and cell wall associated proteins plus others encoding regulatory proteins The RNAIII transcript also encodes the 26 amino acid δ-haemolysin peptide (Hld). RNAIII contains many stem loops, most of which match the Shine-Dalgarno sequence involved in translation initiation of the regulated genes. Some of these interactions are inhibitory, others stimulatory; among the former is the regulatory protein Rot. In vitro, RNAIII is expressed post exponentially, inhibiting translation of the surface proteins, notably protein A, while stimulating that of the exoproteins, many of which are tissue-degrading enzymes or cytolysins. Among the latter is the important virulence factor, α-hemolysin (Hla), whose translation RNAIII activates by preventing the formation of an inhibitory foldback loop in the hla mRNA leader.

Lysostaphin is a Staphylococcus simulans metalloendopeptidase. It can function as a bacteriocin (antimicrobial) against Staphylococcus aureus.

Phenol-soluble modulins (PSMs) are a family of small proteins, that carry out a variety of functions, including acting as toxins, assisting in biofilm formation, and colony spreading. PSMs are produced by Staphylococcus bacteria including Methicillin-resistant Staphylococcus aureus (MRSA), and Staphylococcus epidermidis. Many PSMs are encoded within the core genome and can play an important virulence factor. PSMs were first discovered in S. epidermidis by Seymour Klebanoff and via hot-phenol extraction and were described as a pro-inflammatory complex of three peptides. Since their initial discovery, numerous roles of PSMs have been identified. However, due in part to the small size of many PSMs, they have largely gone unnoticed until recent years.

<span class="mw-page-title-main">Cathepsin L1</span> Protein-coding gene in the species Homo sapiens

Cathepsin L1 is a protein that in humans is encoded by the CTSL1 gene. The protein is a cysteine cathepsin, a lysosomal cysteine protease that plays a major role in intracellular protein catabolism.

<span class="mw-page-title-main">Cystatin A</span> Protein-coding gene in the species Homo sapiens

Cystatin-A is a protein that in humans is encoded by the CSTA gene.

mecA is a gene found in bacterial cells which allows them to be resistant to antibiotics such as methicillin, penicillin and other penicillin-like antibiotics.

'Staphylococcus aureus delta toxin is a toxin produced by Staphylococcus aureus. It has a wide spectrum of cytolytic activity.

<i>Staphylococcus</i> Genus of Gram-positive bacteria

Staphylococcus is a genus of Gram-positive bacteria in the family Staphylococcaceae from the order Bacillales. Under the microscope, they appear spherical (cocci), and form in grape-like clusters. Staphylococcus species are facultative anaerobic organisms.

SaPIs are a family of ~15 kb mobile genetic elements resident in the genomes of the vast majority of S. aureus strains. Much like bacteriophages, SaPIs can be transferred to uninfected cells and integrate into the host chromosome. Unlike the bacterial viruses, however, integrated SaPIs are mobilized by host infection with "helper" bacteriophages. SaPIs are used by the host bacteria to co-opt the phage reproduction cycle for their own genetic transduction and also inhibit phage reproduction in the process.

<span class="mw-page-title-main">Glutamyl endopeptidase GluV8</span>

Glutamyl endopeptidase is an extracellular bacterial serine protease of the glutamyl endopeptidase I family that was initially isolated from the Staphylococcus aureus strain V8. The protease is, hence, commonly referred to as "V8 protease", or alternatively SspA from its corresponding gene.

Staphopain is an enzyme. This enzyme catalyses the following chemical reaction

<span class="mw-page-title-main">Aureolysin</span>

Aureolysin is an extracellular metalloprotease expressed by Staphylococcus aureus. This protease is a major contributor to the bacterium's virulence, or ability to cause disease, by cleaving host factors of the innate immune system as well as regulating S. aureus secreted toxins and cell wall proteins. To catalyze its enzymatic activities, aureolysin requires zinc and calcium which it obtains from the extracellular environment within the host.

Staphylococcus pseudintermedius is a gram positive coccus bacteria of the genus Staphylococcus found worldwide. It is primarily a pathogen for domestic animals, but has been known to affect humans as well. S. pseudintermedius is an opportunistic pathogen that secretes immune modulating virulence factors, has many adhesion factors, and the potential to create biofilms, all of which help to determine the pathogenicity of the bacterium. Diagnoses of Staphylococcus pseudintermedius have traditionally been made using cytology, plating, and biochemical tests. More recently, molecular technologies like MALDI-TOF, DNA hybridization and PCR have become preferred over biochemical tests for their more rapid and accurate identifications. This includes the identification and diagnosis of antibiotic resistant strains.

Glutamyl endopeptidase I is a family of extracellular bacterial serine proteases. The proteases within this family have been identified in species of Staphylococcus, Bacillus, and Streptomyces, among others. The two former are more closely related, while the Streptomyces-type is treated as a separate family, glutamyl endopeptidase II.

References

  1. 1 2 3 4 5 6 7 Kantyka T, Shaw LN, Potempa J (January 2013). Rawlings ND, Salvesen G (eds.). Handbook of Proteolytic Enzymes. Academic Press. pp. 2150–2157. doi:10.1016/b978-0-12-382219-2.00483-x. ISBN   9780123822192.
  2. 1 2 3 4 5 6 Dubin G (July 2002). "Extracellular proteases of Staphylococcus spp". Biological Chemistry. 383 (7–8): 1075–86. doi:10.1515/BC.2002.116. PMID   12437090.
  3. 1 2 Filipek R, Rzychon M, Oleksy A, Gruca M, Dubin A, Potempa J, Bochtler M (October 2003). "The Staphostatin-staphopain complex: a forward binding inhibitor in complex with its target cysteine protease". The Journal of Biological Chemistry. 278 (42): 40959–66. doi: 10.1074/jbc.M302926200 . PMID   12874290.
  4. 1 2 3 4 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.
  5. ↑ 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.
  6. ↑ Lindsay JA, Foster SJ (September 1999). "Interactive regulatory pathways control virulence determinant production and stability in response to environmental conditions in Staphylococcus aureus". Molecular & General Genetics. 262 (2): 323–31. doi:10.1007/s004380051090. PMID   10517329.
  7. ↑ Zdzalik M, Karim AY, Wolski K, Buda P, Wojcik K, Brueggemann S, Wojciechowski P, Eick S, Calander AM, Jonsson IM, Kubica M, Polakowska K, Miedzobrodzki J, Wladyka B, Potempa J, Dubin G (November 2012). "Prevalence of genes encoding extracellular proteases in Staphylococcus aureus - important targets triggering immune response in vivo". FEMS Immunology and Medical Microbiology. 66 (2): 220–9. doi: 10.1111/j.1574-695X.2012.01005.x . PMID   22762789.
  8. 1 2 Nickerson N, Ip J, Passos DT, McGavin MJ (January 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". Molecular Microbiology. 75 (1): 161–77. doi: 10.1111/j.1365-2958.2009.06974.x . PMID   19943908.
  9. ↑ Dubin G (January 2003). "Defense against own arms: staphylococcal cysteine proteases and their inhibitors" (PDF). Acta Biochimica Polonica. 50 (3): 715–24. doi:10.18388/abp.2003_3662. PMID   14515151.
  10. 1 2 Potempa J, Dubin A, Korzus G, Travis J (February 1988). "Degradation of elastin by a cysteine proteinase from Staphylococcus aureus". The Journal of Biological Chemistry. 263 (6): 2664–7. doi: 10.1016/S0021-9258(18)69118-5 . PMID   3422637.
  11. 1 2 Jusko M, Potempa J, Kantyka T, Bielecka E, Miller HK, Kalinska M, Dubin G, Garred P, Shaw LN, Blom AM (January 2014). "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.
  12. ↑ Laarman AJ, Mijnheer G, Mootz JM, van Rooijen WJ, Ruyken M, Malone CL, Heezius EC, Ward R, Milligan G, van Strijp JA, de Haas CJ, Horswill AR, van Kessel KP, Rooijakkers SH (August 2012). "Staphylococcus aureus Staphopain A inhibits CXCR2-dependent neutrophil activation and chemotaxis". The EMBO Journal. 31 (17): 3607–19. doi:10.1038/emboj.2012.212. PMC   3433787 . PMID   22850671.
  13. ↑ Takahashi M, Tezuka T, Korant B, Katunuma N (January 1999). "Inhibition of cysteine protease and growth of Staphylococcus aureus V8 and poliovirus by phosphorylated cystatin alpha conjugate of skin". BioFactors. 10 (4): 339–45. doi:10.1002/biof.5520100404. PMID   10619701.
  14. ↑ Kasprzykowski F, Schalén C, Kasprzykowska R, Jastrzebska B, Grubb A (July 2000). "Synthesis and antibacterial properties of peptidyl derivatives and cyclopeptides structurally based upon the inhibitory centre of human cystatin C. Dissociation of antiproteolytic and antibacterial effects". APMIS . 108 (7–8): 473–81. doi:10.1034/j.1600-0463.2000.d01-85.x (inactive 2024-04-25). PMID   11167542.{{cite journal}}: CS1 maint: DOI inactive as of April 2024 (link)
  15. ↑ Calander AM, Jonsson IM, Kanth A, Arvidsson S, Shaw L, Foster SJ, Tarkowski A (February 2004). "Impact of staphylococcal protease expression on the outcome of infectious arthritis". Microbes and Infection. 6 (2): 202–6. doi:10.1016/j.micinf.2003.10.015. PMID   14998519.
  16. ↑ Mootz JM, Malone CL, Shaw LN, Horswill AR (September 2013). "Staphopains modulate Staphylococcus aureus biofilm integrity". Infection and Immunity. 81 (9): 3227–38. doi:10.1128/IAI.00377-13. PMC   3754231 . PMID   23798534.
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