Glutamyl endopeptidase (, ''SspA, V8 protease, GluV8,'' ''endoproteinase Glu-C'', ''staphylococcal serine proteinase'') is an extracellular bacterial serine protease of the

glutamyl endopeptidase I 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 close ...

family that was initially isolated from the ''

Staphylococcus aureus ''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 ...

'' strain V8. The protease is, hence, commonly referred to as "V8 protease", or alternatively SspA from its corresponding gene.

Genetics

Glutamyl endopeptidase is in ''S. aureus'' expressed from the gene ''sspA'' within the operon ''ssp''. 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). Glutamyl endopeptidase is largely co-expressed with the other major proteases of ''S. aureus'':

aureolysin Aureolysin (, ''protease III, staphylococcal metalloprotease,'' ''Staphylococcus aureus neutral proteinase'') is an extracellular metalloprotease expressed by ''Staphylococcus aureus''. This protease is a major contributor to the bacterium's virule ...

, staphopain A, and staphopain B. The transcription of ''ssp'', that occurs via a promoter controlled by " housekeeping"

sigma factor A sigma factor (σ factor or specificity factor) is a protein needed for initiation of transcription in bacteria. It is a bacterial transcription initiation factor that enables specific binding of RNA polymerase (RNAP) to gene promoters. It is ho ...

σ^A, is up-regulated by accessory gene regulator ''agr'', while it is repressed by staphylococcal accessory regulator ''sarA'' and by alternative sigma factor σ^B (a stress response modulator of

Gram-positive bacteria In bacteriology, gram-positive bacteria are bacteria that give a positive result in the Gram stain test, which is traditionally used to quickly classify bacteria into two broad categories according to their type of cell wall. Gram-positive bact ...

). ''ssp'' expression is highly expressed in post-exponential growth phase. A more complex network of modulators and of environmental conditions affecting ''ssp'' expression have been suggested, however. The ''sspA'' gene has a high prevalence in the genome of both commensal- and

pathogenic In biology, a pathogen ( el, πάθος, "suffering", "passion" and , "producer of") in the oldest and broadest sense, is any organism or agent that can produce disease. A pathogen may also be referred to as an infectious agent, or simply a germ ...

-type ''S. aureus'' strains.

Activation

Glutamyl endopeptidase is expressed as a zymogen that, in order to become fully active, has been modified both through autocatalysis and through cleavage by the metalloprotease

Function

Glutamyl endopeptidase proteolytically activates the zymogen of the cysteine protease staphopain B (staphopain A is activated through and independent process). The bacterial protease has a narrow specificity, with a strict preference for catalyzing hydrolysis of proteins after negatively charged amino acids, especially

glutamic acid Glutamic acid (symbol Glu or E; the ionic form is known as glutamate) is an α-amino acid that is used by almost all living beings in the biosynthesis of proteins. It is a non-essential nutrient for humans, meaning that the human body can synt ...

, and to some extent

aspartic acid Aspartic acid (symbol Asp or D; the ionic form is known as aspartate), is an α-amino acid that is used in the biosynthesis of proteins. Like all other amino acids, it contains an amino group and a carboxylic acid. Its α-amino group is in the pro ...

. 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. Glutamyl endopeptidase can inhibit the activation of targets within the

complement system The complement system, also known as complement cascade, is a part of the immune system that enhances (complements) the ability of antibodies and phagocytic cells to clear microbes and damaged cells from an organism, promote inflammation, and at ...

. It is indicated to cause inhibition to all three pathways of complement activation. 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.

Biological significance

An immunization survey of human

serum Serum may refer to: *Serum (blood), plasma from which the clotting proteins have been removed **Antiserum, blood serum with specific antibodies for passive immunity * Serous fluid, any clear bodily fluid * Truth serum, a drug that is likely to mak ...

samples suggests that exposure to 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 Virulence factors (preferably known as pathogenicity factors or effectors in plant science) are cellular structures, molecules and regulatory systems that enable microbial pathogens (bacteria, viruses, fungi, and protozoa) to achieve the following ...

and their

genetic regulation Regulation of gene expression, or gene regulation, includes a wide range of mechanisms that are used by cells to increase or decrease the production of specific gene products (protein or RNA). Sophisticated programs of gene expression are wide ...

, 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. Glutamyl endopeptidase is indicated to participate in control and dissemination in bacterial biofilms. The protease can contribute to infection

symptom Signs and symptoms are the observed or detectable signs, and experienced symptoms of an illness, injury, or condition. A sign for example may be a higher or lower temperature than normal, raised or lowered blood pressure or an abnormality showin ...

s, e.g. pain and edema through increased vascular permeability by activating kinin. De-regulation of neutrophil proteases through inactivation of α₁-antitrypsin has been suggested as a potential cause of dysfunctional coagulation in sepsis.

References

External links

* ''Staphylococcus aureus'' {{Portal bar, Biology, border=no EC 3.4.21 Proteases Hydrolases