Cathepsin G is a protein that in humans is encoded by the CTSGgene. It is one of the three serine proteases of the chymotrypsin family that are stored in the azurophil granules, and also a member of the peptidase S1 protein family. Cathepsin G plays an important role in eliminating intracellular pathogens and breaking down tissues at inflammatory sites, as well as in anti-inflammatory response.[1][2][3][4]
The CTSG gene is located at chromosome 14q11.2, consisting of 5 exons. Each residue of the catalytic triad is located on a separate exon. Five polymorphisms have been identified by scanning the entire coding region.[5] Cathepsin G is one of those homologous protease that evolved from a common ancestor by gene duplication.[6]
Protein
Cathepsin G is a 255-amino-acid-residue protein including an 18-residue signal peptide, a two-residue activation peptide at the N-terminus and a carboxy terminal extension.[7] The activity of cathepsin G depends on a catalytic triad composed of aspartate, histidine and serine residues which are widely separated in the primary sequence but close to each other at the active site of the enzyme in the tertiary structure.[8]
Function
Cathepsin G has a specificity similar to that of chymotrypsin C, but it is most closely related to other immune serine proteases, such as neutrophil elastase and the granzymes.[9] As a neutrophil serine protease, was first identified as degradative enzyme that acts intracellularly to degrade ingested host pathogens and extracellularly in the breakdown of ECM components at inflammatory sites.[10] It localizes to Neutrophil extracellular traps (NETs), via its high affinity for DNA, an unusual property for serine proteases.[9] Transcript variants utilizing alternative polyadenylation signals exist for this gene.[11] Cathepsin G was also found to exert broad-spectrum antibacterial action against Gram-negative and –positive bacteria independent of the function mentioned above.[12] Other functions of cathepsin G have been reported, including cleavage of receptors, conversion of angiotensin Ⅰ to angiotensin Ⅱ, platelet activation, and induction of airway submucosal gland secretion.[13][14][15][16][17] Potential implications of the enzyme in blood-brain barrier breakdown was also found.[18]
Clinical significance
Cathepsin G has been reported to play an important role in a variety of diseases, including rheumatoid arthritis, coronary artery disease, periodontitis, ischemic reperfusion injury, and bone metastasis.[19][20][21][22][23] It is also implicated in a variety of infectious inflammatory diseases, including chronic obstructive pulmonary disease, acute respiratory distress syndrome, and cystic fibrosis.[24][25][26] A recent study shows that patients with CTSG gene polymorphisms have higher risk of chronic postsurgical pain, suggesting cathepsin G may serve as a novel target for pain control and a potential marker to predict chronic postsurgical pain.[27] An upregulation of cathepsin G was reported in studies of keratoconus.[28]
↑Baggiolini M, Schnyder J, Bretz U, Dewald B, Ruch W (1979). "Cellular mechanisms of proteinase release from inflammatory cells and the degradation of extracellular proteins". Ciba Foundation Symposium (75): 105–21. PMID399884.
↑Virca GD, Metz G, Schnebli HP (October 1984). "Similarities between human and rat leukocyte elastase and cathepsin G". European Journal of Biochemistry / FEBS. 144 (1): 1–9. doi:10.1111/j.1432-1033.1984.tb08423.x. PMID6566611.
↑Herrmann SM, Funke-Kaiser H, Schmidt-Petersen K, Nicaud V, Gautier-Bertrand M, Evans A, Kee F, Arveiler D, Morrison C, Orzechowski HD, Elbaz A, Amarenco P, Cambien F, Paul M (September 2001). "Characterization of polymorphic structure of cathepsin G gene: role in cardiovascular and cerebrovascular diseases". Arteriosclerosis, Thrombosis, and Vascular Biology. 21 (9): 1538–43. doi:10.1161/hq0901.095555. PMID11557685.
↑Salvesen G, Enghild JJ (1991). "Zymogen activation specificity and genomic structures of human neutrophil elastase and cathepsin G reveal a new branch of the chymotrypsinogen superfamily of serine proteinases". Biomedica Biochimica Acta. 50 (4–6): 665–71. PMID1801740.
↑Salvesen G, Farley D, Shuman J, Przybyla A, Reilly C, Travis J (April 1987). "Molecular cloning of human cathepsin G: structural similarity to mast cell and cytotoxic T lymphocyte proteinases". Biochemistry. 26 (8): 2289–93. doi:10.1021/bi00382a032. PMID3304423.
↑Korkmaz B, Moreau T, Gauthier F (February 2008). "Neutrophil elastase, proteinase 3 and cathepsin G: physicochemical properties, activity and physiopathological functions". Biochimie. 90 (2): 227–42. doi:10.1016/j.biochi.2007.10.009. PMID18021746.
↑Shafer WM, Pohl J, Onunka VC, Bangalore N, Travis J (January 1991). "Human lysosomal cathepsin G and granzyme B share a functionally conserved broad spectrum antibacterial peptide". The Journal of Biological Chemistry. 266 (1): 112–6. PMID1985886.
↑Beaufort N, Leduc D, Rousselle JC, Magdolen V, Luther T, Namane A, Chignard M, Pidard D (January 2004). "Proteolytic regulation of the urokinase receptor/CD87 on monocytic cells by neutrophil elastase and cathepsin G". Journal of Immunology. 172 (1): 540–9. doi:10.4049/jimmunol.172.1.540. PMID14688365.
↑Bank U, Ansorge S (February 2001). "More than destructive: neutrophil-derived serine proteases in cytokine bioactivity control". Journal of Leukocyte Biology. 69 (2): 197–206. PMID11272269.
↑Reilly CF, Tewksbury DA, Schechter NM, Travis J (August 1982). "Rapid conversion of angiotensin I to angiotensin II by neutrophil and mast cell proteinases". The Journal of Biological Chemistry. 257 (15): 8619–22. PMID6807977.
↑Sambrano GR, Huang W, Faruqi T, Mahrus S, Craik C, Coughlin SR (March 2000). "Cathepsin G activates protease-activated receptor-4 in human platelets". The Journal of Biological Chemistry. 275 (10): 6819–23. doi:10.1074/jbc.275.10.6819. PMID10702240.
↑Nadel JA (September 1991). "Role of mast cell and neutrophil proteases in airway secretion". The American Review of Respiratory Disease. 144 (3 Pt 2): S48–51. doi:10.1164/ajrccm/144.3_pt_2.S48. PMID1892327.
↑Armao D, Kornfeld M, Estrada EY, Grossetete M, Rosenberg GA (September 1997). "Neutral proteases and disruption of the blood-brain barrier in rat". Brain Research. 767 (2): 259–64. doi:10.1016/S0006-8993(97)00567-2. PMID9367256.
↑Szekanecz Z, Koch AE (May 2007). "Macrophages and their products in rheumatoid arthritis". Current Opinion in Rheumatology. 19 (3): 289–95. doi:10.1097/BOR.0b013e32805e87ae. PMID17414958.
↑Takei T, Sakai S, Yokonuma T, Ijima H, Kawakami K (Jan–Feb 2007). "Fabrication of artificial endothelialized tubes with predetermined three-dimensional configuration from flexible cell-enclosing alginate fibers". Biotechnology Progress. 23 (1): 182–6. doi:10.1021/bp060152j. PMID17269686.
↑Kawabata K, Hagio T, Matsuoka S (September 2002). "The role of neutrophil elastase in acute lung injury". European Journal of Pharmacology. 451 (1): 1–10. doi:10.1016/s0014-2999(02)02182-9. PMID12223222.
↑Liu X, Tian Y, Meng Z, Chen Y, Ho IH, Choy KW, Lichtner P, Wong SH, Yu J, Gin T, Wu WK, Cheng CH, Chan MT (October 2015). "Up-regulation of Cathepsin G in the Development of Chronic Postsurgical Pain: An Experimental and Clinical Genetic Study". Anesthesiology. 123 (4): 838–50. doi:10.1097/ALN.0000000000000828. PMID26270939.
↑Son ED, Shim JH, Choi H, Kim H, Lim KM, Chung JH, Byun SY, Lee TR (2012). "Cathepsin G inhibitor prevents ultraviolet B-induced photoaging in hairless mice via inhibition of fibronectin fragmentation". Dermatology. 224 (4): 352–60. doi:10.1159/000339337. PMID22759782.
↑Cruz-Silva I, Neuhof C, Gozzo AJ, Nunes VA, Hirata IY, Sampaio MU, Figueiredo-Ribeiro Rde C, Neuhof H, Araújo Mda S (December 2013). "Using a Caesalpinia echinata Lam. protease inhibitor as a tool for studying the roles of neutrophil elastase, cathepsin G and proteinase 3 in pulmonary edema". Phytochemistry. 96: 235–43. doi:10.1016/j.phytochem.2013.09.025. PMID24140156.
↑Craciun I, Fenner AM, Kerns RJ (February 2016). "N-Arylacyl O-sulfonated aminoglycosides as novel inhibitors of human neutrophil elastase, cathepsin G and proteinase 3". Glycobiology. 26: 701–9. doi:10.1093/glycob/cww011. PMID26850997.
Shafer WM, Katzif S, Bowers S, Fallon M, Hubalek M, Reed MS, Veprek P, Pohl J (2002). "Tailoring an antibacterial peptide of human lysosomal cathepsin G to enhance its broad-spectrum action against antibiotic-resistant bacterial pathogens". Current Pharmaceutical Design. 8 (9): 695–702. doi:10.2174/1381612023395376. PMID11945165.
Cohen AB, Stevens MD, Miller EJ, Atkinson MA, Mullenbach G (August 1992). "Generation of the neutrophil-activating peptide-2 by cathepsin G and cathepsin G-treated human platelets". The American Journal of Physiology. 263 (2 Pt 1): L249–56. PMID1387511.
Sasaki T, Ueno-Matsuda E (December 1992). "Immunocytochemical localization of cathepsins B and G in odontoclasts of human deciduous teeth". Journal of Dental Research. 71 (12): 1881–4. doi:10.1177/00220345920710120501. PMID1452887.
Maison CM, Villiers CL, Colomb MG (August 1991). "Proteolysis of C3 on U937 cell plasma membranes. Purification of cathepsin G". Journal of Immunology. 147 (3): 921–6. PMID1861080.
Brandt E, Van Damme J, Flad HD (July 1991). "Neutrophils can generate their activator neutrophil-activating peptide 2 by proteolytic cleavage of platelet-derived connective tissue-activating peptide III". Cytokine. 3 (4): 311–21. doi:10.1016/1043-4666(91)90499-4. PMID1873479.
Kargi HA, Campbell EJ, Kuhn C (August 1990). "Elastase and cathepsin G of human monocytes: heterogeneity and subcellular localization to peroxidase-positive granules". The Journal of Histochemistry and Cytochemistry. 38 (8): 1179–86. doi:10.1177/38.8.2164060. PMID2164060.
Pratt CW, Tobin RB, Church FC (April 1990). "Interaction of heparin cofactor II with neutrophil elastase and cathepsin G". The Journal of Biological Chemistry. 265 (11): 6092–7. PMID2318847.
Hohn PA, Popescu NC, Hanson RD, Salvesen G, Ley TJ (August 1989). "Genomic organization and chromosomal localization of the human cathepsin G gene". The Journal of Biological Chemistry. 264 (23): 13412–9. PMID2569462.
Livesey SA, Buescher ES, Krannig GL, Harrison DS, Linner JG, Chiovetti R (1989). "Human neutrophil granule heterogeneity: immunolocalization studies using cryofixed, dried and embedded specimens". Scanning Microscopy. Supplement. 3: 231–9, discussion 239–40. PMID2616953.
Campbell EJ, Silverman EK, Campbell MA (November 1989). "Elastase and cathepsin G of human monocytes. Quantification of cellular content, release in response to stimuli, and heterogeneity in elastase-mediated proteolytic activity". Journal of Immunology. 143 (9): 2961–8. PMID2681419.
Salvesen G, Farley D, Shuman J, Przybyla A, Reilly C, Travis J (April 1987). "Molecular cloning of human cathepsin G: structural similarity to mast cell and cytotoxic T lymphocyte proteinases". Biochemistry. 26 (8): 2289–93. doi:10.1021/bi00382a032. PMID3304423.
Heck LW, Rostand KS, Hunter FA, Bhown A (October 1986). "Isolation, characterization, and amino-terminal amino acid sequence analysis of human neutrophil cathepsin G from normal donors". Analytical Biochemistry. 158 (1): 217–27. doi:10.1016/0003-2697(86)90612-3. PMID3799965.
Crocker J, Jenkins R, Burnett D (May 1985). "Immunohistochemical localization of cathepsin G in human tissues". The American Journal of Surgical Pathology. 9 (5): 338–43. doi:10.1097/00000478-198505000-00003. PMID3911778.
Klickstein LB, Kaempfer CE, Wintroub BU (December 1982). "The granulocyte-angiotensin system. Angiotensin I-converting activity of cathepsin G". The Journal of Biological Chemistry. 257 (24): 15042–6. PMID6294088.
LaRosa CA, Rohrer MJ, Benoit SE, Barnard MR, Michelson AD (July 1994). "Neutrophil cathepsin G modulates the platelet surface expression of the glycoprotein (GP) Ib-IX complex by proteolysis of the von Willebrand factor binding site on GPIb alpha and by a cytoskeletal-mediated redistribution of the remainder of the complex". Blood. 84 (1): 158–68. PMID7517206.
Savage MJ, Iqbal M, Loh T, Trusko SP, Scott R, Siman R (June 1994). "Cathepsin G: localization in human cerebral cortex and generation of amyloidogenic fragments from the beta-amyloid precursor protein". Neuroscience. 60 (3): 607–19. doi:10.1016/0306-4522(94)90490-1. PMID7936190.
Maruyama K, Sugano S (January 1994). "Oligo-capping: a simple method to replace the cap structure of eukaryotic mRNAs with oligoribonucleotides". Gene. 138 (1–2): 171–4. doi:10.1016/0378-1119(94)90802-8. PMID8125298.
External links
The MEROPS online database for peptidases and their inhibitors: S01.133