Alternative titles; symbols
HGNC Approved Gene Symbol: CTSG
Cytogenetic location: 14q12 Genomic coordinates (GRCh38): 14:24,573,518-24,576,250 (from NCBI)
Neutrophilic polymorphonuclear leukocytes contain specialized azurophil granules whose contents, including the serine proteases cathepsin G and elastase, may participate in the killing and digestion of engulfed pathogens, and in connective tissue remodeling at sites of inflammation. Cathepsin G is a 26,000-Da protease. Using mRNA from a leukemic cell line, Salvesen et al. (1987) isolated and determined the sequence of a cDNA clone encoding CTSG.
Using human CTSG cDNA as a probe, Heusel et al. (1993) cloned and characterized a novel related murine hematopoietic serine protease gene which was highly homologous to the human gene at nucleotide and amino acid levels.
Hohn et al. (1989) found that the CTSG gene spans 2.7 kb of genomic DNA and consists of 5 exons and 4 introns. The genomic organization is similar to that of neutrophil elastase.
Using in situ hybridization, Hohn et al. (1989) localized the CTSG gene to 14q11.2. Heusel et al. (1993) assigned the Ctsg gene to mouse chromosome 14, tightly linked to the Ctla1 gene.
In transgenic mice, Grisolano et al. (1994) found that the human CTSG gene was expressed in early myeloid precursors in a manner coordinate with the expression of the endogenous murine gene in the bone marrow and spleen.
The antiinflammatory properties of preparations of frankincense, a gum resin derived from Boswellia species, are largely due to boswellic acids (BAs). Using BA affinity chromatography, Tausch et al. (2009) showed selective precipitation of a 26-kD protein from neutrophils that they identified as CATG by mass spectrometry and Western blot analysis. Automated docking analysis revealed that BAs bound, like synthetic inhibitors, to the active center of CATG. BAs potently and reversibly suppressed the activity of CATG, whereas related serine proteases, including leukocyte elastase (ELANE; 130130), chymotrypsin (see CTRB1; 118890), and proteinase-3 (PRTN3; 177020), were much less sensitive to BAs, and others, including tryptase (see TPSAB1; 191080) and chymase (CMA1; 118938), were not affected by BAs at all. BAs did not inhibit neutrophil chemotaxis, but they inhibited invasion through a synthetic matrix. They also inhibited Ca(2+) mobilization in platelets induced by CATG. Oral administration of frankincense extracts to healthy volunteers reduced CATG activity in blood ex vivo. Tausch et al. (2009) concluded that CATG is a functional and pharmacologically relevant target of BAs and that interference with CATG may explain some of the antiinflammatory properties of frankincense.
Using a mouse model of acute inflammation, Chmelar et al. (2011) found that a salivary protein, termed Irs2, from the tick Ixodes ricinus, the vector for Lyme disease in Europe, inhibited edema formation and neutrophil influx in inflamed tissue. Using a panel of human proteins, they found that Irs2 primarily inhibited CTSG and CMA1. Human platelet aggregation assays showed that Irs2 inhibited CTSG-induced and thrombin (F2; 176930)-induced platelet aggregation. Structural analysis revealed that Irs2 resembles mammalian serpins, including bovine antithrombin III (SERPINC1; 107300) and human alpha-1-antichymotrypsin (SERPINA3; 107280) and alpha-1-antitrypsin (SERPINA1; 107400).
Since one form of Alzheimer disease, AD3 (607822), maps to 14q24.3, the lysosomal serine protease cathepsin G, which also maps to 14q, is a candidate for the site of the mutation. A defect in the cellular processing of amyloid precursor protein in familial Alzheimer disease has been postulated. Wong et al. (1993) analyzed the nucleotide sequence of the entire open reading frame of the CTSG gene and found no abnormality in 1 clinically affected member from each of 5 large FAD pedigrees that showed significant or nearly significant lod scores with one or more markers on chromosome 14. The sequence was compared with that of his/her unaffected living parent in each case and no differences were found.
Using mice deficient in Ctsg and/or Ela2 (130130), Reeves et al. (2002) confirmed data originally generated by Tkalcevic et al. (2000) and Belaaouaj et al. (1998) that Ctsg -/- mice resist Candida but not Staphylococcal infection, whereas the reverse is true in Ela2 -/- mice. Both organisms were more virulent in double-knockout mice. Purified neutrophils from these mice mirrored these results in vitro in spite of exhibiting normal phagocytosis, degranulation, oxidase activity, superoxide production, and myeloperoxidase (MPO; 606989) activity. Reeves et al. (2002) hypothesized that reactive oxygen species (ROS) and proteases act together since deficiencies in either lead to comparable reductions in killing efficiency. They determined that conditions in the phagocytic vacuole after activation provoke the influx of enormous concentrations of ROS compensated by a surge of K+ ions crossing the membrane in a pH-dependent manner. The resulting rise in ionic strength induces the release of cationic granule proteins, including Ctsg and Ela2, from the highly charged anionic sulfated proteoglycan matrix within the granules. Reeves et al. (2002) concluded that it is essential for the volume of the vacuole to be restricted for the requisite hypertonicity to develop. They proposed that disruption of the integrity of the cytoskeletal network by microbial products could offer a mechanism of virulence by inhibiting the activation of granule proteins. They also suggested that a role of MPO may be to protect proteases, notably CTSG, from oxidative damage. In a commentary, Gratzer (2002) noted that mycobacteria may evade the innate immune response by their ability to disrupt actin filaments as demonstrated by Guerin and de Chastellier (2000).
Belaaouaj, A., McCarthy, R., Baumann, M., Gao, Z., Ley, T. J., Abraham, S. N., Shapiro, S. D. Mice lacking neutrophil elastase reveal impaired host defense against gram negative bacterial sepsis. Nature Med. 4: 615-618, 1998. [PubMed: 9585238] [Full Text: https://doi.org/10.1038/nm0598-615]
Chmelar, J., Oliveira, C. J., Rezacova, P., Francischetti, I. M. B., Kovarova, Z., Pejler, G., Kopacek, P., Ribeiro, J. M. C., Mares, M., Kopecky, J., Kotsyfakis, M. A tick salivary protein targets cathepsin G and chymase and inhibits host inflammation and platelet aggregation. Blood 117: 736-744, 2011. [PubMed: 20940421] [Full Text: https://doi.org/10.1182/blood-2010-06-293241]
Gratzer, W. Immunology: the Wright stuff. Nature 416: 275-277, 2002. [PubMed: 11907564] [Full Text: https://doi.org/10.1038/416275a]
Grisolano, J. L., Sclar, G. M., Ley, T. J. Early myeloid cell-specific expression of the human cathepsin G gene in transgenic mice. Proc. Nat. Acad. Sci. 91: 8989-8993, 1994. [PubMed: 8090757] [Full Text: https://doi.org/10.1073/pnas.91.19.8989]
Guerin, I., de Chastellier, C. Pathogenic mycobacteria disrupt the macrophage actin filament network. Infect. Immun. 68: 2655-2662, 2000. [PubMed: 10768957] [Full Text: https://doi.org/10.1128/IAI.68.5.2655-2662.2000]
Heusel, J. W., Scarpati, E. M., Jenkins, N. A., Gilbert, D. J., Copeland, N. G., Shapiro, S. D., Ley, T. J. Molecular cloning, chromosomal location, and tissue-specific expression of the murine cathepsin G gene. Blood 81: 1614-1623, 1993. [PubMed: 8453108]
Hohn, P. A., Popescu, N. C., Hanson, R. D., Salvesen, G., Ley, T. J. Genomic organization and chromosomal localization of the human cathepsin G gene. J. Biol. Chem. 264: 13412-13419, 1989. [PubMed: 2569462]
Reeves, E. P., Lu, H., Jacobs, H. L., Messina, C. G. M., Bolsover, S., Gabella, G., Potma, E. O., Warley, A., Roes, J., Segal, A. W. Killing activity of neutrophils is mediated through activation of proteases by K+ flux. Nature 416: 291-297, 2002. [PubMed: 11907569] [Full Text: https://doi.org/10.1038/416291a]
Salvesen, G., Farley, D., Shuman, J., Przybyla, A., Reilly, C., Travis, J. Molecular cloning of human cathepsin G: structural similarity to mast cell and cytotoxic T lymphocyte proteinases. Biochemistry 26: 2289-2293, 1987. [PubMed: 3304423] [Full Text: https://doi.org/10.1021/bi00382a032]
Tausch, L., Henkel, A., Siemoneit, U., Poeckel, D., Kather, N., Franke, L., Hofmann, B., Schneider, G., Angioni, C., Geisslinger, G., Skarke, C., Holtmeier, W., Beckhaus, T., Karas, M., Jauch, J., Werz, O. Identification of human cathepsin G as a functional target of boswellic acids from the anit-inflammatory remedy frankincense. J. Immun. 183: 3433-3442, 2009. [PubMed: 19648270] [Full Text: https://doi.org/10.4049/jimmunol.0803574]
Tkalcevic, J., Novelli, M., Phylactides, M., Iredale, J. P., Segal, A. W., Roes, J. Impaired immunity and enhanced resistance to endotoxin in the absence of neutrophil elastase and cathepsin G. Immunity 12: 201-210, 2000. [PubMed: 10714686] [Full Text: https://doi.org/10.1016/s1074-7613(00)80173-9]
Wong, L., Liang, Y., Jiang, L., Tsuda, T., Fong, Q., Galway, G., Alexandrova, N., Rogaeva, E., Lukiw, W., Smith, J., Rogaev, E., Crapper McLachlan, D., St. George-Hyslop, P. Mutation of the gene for the human lysosomal serine protease cathepsin G is not the cause of aberrant APP processing in familial Alzheimer disease. Neurosci. Lett. 152: 96-98, 1993. [PubMed: 8515885] [Full Text: https://doi.org/10.1016/0304-3940(93)90492-4]