Glutamyl endopeptidase is in S. aureus expressed from the
genesspA within the
operonssp.
Downstream of sspA, the operon also includes the genes of the
cysteine protease staphopain B (sspB) and of staphostatin B (sspC; specific inhibitor of staphopain B).[4][5]
Glutamyl endopeptidase is largely co-expressed with the other major proteases of S. aureus:
aureolysin,
staphopain A, and staphopain B. The transcription of ssp, 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). 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.[6][7]
Glutamyl endopeptidase proteolytically activates the zymogen of the
cysteine protease staphopain B (staphopain A is activated through and independent process).[10][11][12]
The bacterial protease has a narrow specificity, with a strict preference for
catalyzing hydrolysis of proteins after negatively charged amino acids, especially
glutamic acid, and to some extent
aspartic acid.[1][2][13] Aspartic acid is cleaved mainly when followed by a small amino acid, such as glycine.[13]
Glutamyl endopeptidase has been shown to cleave certain target proteins among human inflammatory regulators and immune components. It can process
kininogen into
kinin, and cleave
immunoglobulins. The protease also cleaves and inactivates
α1-antitrypsin, but is successfully inhibited by
α2-macroglubulin.[1] Glutamyl endopeptidase can inhibit the activation of targets within the
complement system. It is indicated to cause inhibition to all three pathways of complement activation.[14]
Glutamyl endopeptidase can furthermore cleave a wide array bacterial surface proteins, including fibronectin-binding proteins and
protein A, potentially acting as a self-regulatory mechanism.[15][16][17]
Biological significance
An
immunization survey of human
serum samples suggests that exposure to glutamyl endopeptidase is common, although a correlation to any specific type of
infection could not be established.[8] 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. In vivo trials with S. aureus with inactivation of ssp or sspA controlling glutamyl endopeptidase gives a contradictory picture for its importance, although it has shown impact for bacterial survival in human whole blood. It has been suggested, however, that the protease promotes S. aureus dissemination through cleavage of self-proteins and through kinin-induced
vasodilation, simultaneously protecting against immunological responses, i.e. through corruption of the regulation of the complement system and of neutrophil-derived proteases.[1][14][18][19]
Glutamyl endopeptidase is indicated to participate in control and dissemination in bacterial
biofilms.[20]
The protease can contribute to
infectionsymptoms, e.g. pain and edema through increased vascular permeability by activating kinin.[1] De-regulation of neutrophil proteases through inactivation of α1-antitrypsin has been suggested as a potential cause of dysfunctional
coagulation in
sepsis.[21]
^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): 365–380.
doi:
10.1016/j.ijmm.2006.02.019.
PMID16782403.
^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): 323–331.
doi:
10.1007/s004380051090.
PMID10517329.
S2CID29491620.