CTSG

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Introduction

Cathepsin G (CathG, also known as GTSG) is a serine protease, which is considered to be one of the effectors of inflammation and can regulate the function of immune cells. Human CathG combines the properties of trypsin and chymotrypsin, That is, it can cleave the peptide bond formed by the carboxyl group of positively charged (arginine, lysine) and aromatic (leucine, tyrosine, phenylalanine,) amino acid residues. As a component of the neutrophil proteolytic mechanism, CathG regulates the inflammatory response by stimulating the production of chemokines and cytokines, which are responsible for mobilizing immune cells to pathogens and tissue damage sites.

CathG is synthesized by immunocytes in the form of secretion (mast cells, neutrophils), or in the form of intracellular proteins (antigen presenting cells). It is also present in endothelial, smooth muscle cells, brain astrocytes and fibroblasts. The protease can not only act on the innate immune response, that is, participate in the presentation of antigen and the stimulation of specific immune response, etc., it also has good antibacterial properties and plays a role in neutralizing toxins.

CathG is involved in chronic inflammatory processes, such as various neuropathies, atherosclerosis, chronic obstructive pulmonary disease, tumor pathogenesis and development. The final result of CathG-mediated proteolysis may lead to an increase in inflammation response, or conversely, to inflammation suppression. It is essential to maintain the delicate balance between tissue protection and destruction during inflammatory response. This immune protease can not only regulate inflammation, but also participate in normal physiological processes, such as digestion, epithelial renewal, tissue remodeling, smooth muscle contraction, and others. 

Potential Substrates of Cathepsin G in Intestinal Mucosa

Because CathG has the ability to process proteins, the enzyme is likely to participate in the activation of biologically active molecules located in the epithelial layer. The synthesis and secretion of CathG by Paneth cells (PCs) and the observed adsorption of enzymes on the brush border all indicate the possibility of direct contact between CathG and its potential substrates expressed on the surface of the epithelium. Enteropeptidase is a membrane protein of enterocytes. It is responsible for cleaving pancreatic trypsinogen to produce trypsin in the digestion cascade, so that trypsin can activate other pancreatic zymogens. The single-chain precursor of enteropeptidase obviously undergoes proteolytic processing by unknown proteases. Since CathG is a structural and functional analogue of duodenase (potential activator of bovine enteropeptidase), it can be assumed that CathG can activate enteropeptidase. Trypsin from PCs is stored as an inactive zymogen, but its proteolytic activator has not been identified. The enteropeptidase activated by CathG may cleave PCs-derived trypsinogen, which in turn acts as a prodefensin-convertase, contributing to the innate defense of crypts. This gives a promising direction for exploring the connection between digestion and immunity. The link may be a multifunctional regulatory protease, such as CathG, whose functional activity can affect both digestion process and protective immune response.

Discussion

Proteases of the gastrointestinal tract not only participate in the function of the digestive conveyor hydrolyzing nutrients, but also control various physiological processes, including smooth muscle contraction, tissue renewal and remodeling, hormone regulation, and intestinal protection. A new opinion on the role of CathG is associated with the discovery of an alternative source of CathG biosynthesis in the uninflamed intestinal mucosa-specialized epithelial cells-PCs and the secretion of this enzyme in the epithelial zone, where potential CathG substrates are localized.

Available data indicate that CathG has significant biosynthesis in the normal intestinal mucosa, with few neutrophils. The role of CathG may be important in the development of diseases such as inflammatory bowel disease, and its mechanism is still not fully understood. CathG is more known as a neutrophil pro-inflammatory factor, and it is also a constitutive enzyme of normal intestinal mucosa. The protease may be involved in the activation of epithelial proteases, receptors, peptides in the epithelial layer, and in the regulation of normal physiological processes, adaptive and protective functions of duodenum.

Figure 1. CathG-between norm and inflammation: the role of CathG in the intestinal mucosa (Zamolodchikova, T.S.; et al. 2020)