Cathepsin G Explained

Cathepsin G is a protein that in humans is encoded by the CTSG gene. 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]}

Structure

Gene

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.^[4] Cathepsin G is one of those homologous protease that evolved from a common ancestor by gene duplication.^[5]

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.^[6] 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.^[7]

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.^[8] 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.^[9] It localizes to Neutrophil extracellular traps (NETs), via its high affinity for DNA, an unusual property for serine proteases. Transcript variants utilizing alternative polyadenylation signals exist for this gene.^[10] Cathepsin G was also found to exert broad-spectrum antibacterial action against Gram-negative and –positive bacteria independent of the function mentioned above.^[11] 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.^{[12] [13] [14] [15] [16]} Potential implications of the enzyme in blood-brain barrier breakdown was also found.^[17]

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.^{[18] [19] [20] [21] [22]} It is also implicated in a variety of infectious inflammatory diseases, including chronic obstructive pulmonary disease, acute respiratory distress syndrome, and cystic fibrosis.^{[23] [24] [25]} 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.^[26] An upregulation of cathepsin G was reported in studies of keratoconus.^[27]

Interactions

Cathepsin G has been found to interact with:

• SERPINB1^[28]

Cathepsin G is inhibited by:

• [2-[3-[[(1-benzoyl-4-piperidinyl)methylamino]carbonyl]-2-naphthalenyl]-1-(1-naphthalenyl)-2-oxoethyl]-phosphonic acid (KPA) ^[29]
• Caesalpinia echinata elastase inhibitor^[30]
• N-Arylacyl O-sulfonated aminoglycosides^[31]

Cathepsin G lowers levels of:

• Low-density lipoprotein^[32]

See also

• Cathepsins

Further reading

• Shafer WM, Katzif S, Bowers S, Fallon M, Hubalek M, Reed MS, Veprek P, Pohl J . 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 . 2002 . 11945165 . 10.2174/1381612023395376 .
• Cohen AB, Stevens MD, Miller EJ, Atkinson MA, Mullenbach G . 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 . August 1992 . 1387511 . 10.1152/ajplung.1992.263.2.L249.
• Sasaki T, Ueno-Matsuda E . Immunocytochemical localization of cathepsins B and G in odontoclasts of human deciduous teeth . Journal of Dental Research . 71 . 12 . 1881–4 . December 1992 . 1452887 . 10.1177/00220345920710120501 . 27658837 .
• Maison CM, Villiers CL, Colomb MG . Proteolysis of C3 on U937 cell plasma membranes. Purification of cathepsin G . Journal of Immunology . 147 . 3 . 921–6 . August 1991 . 10.4049/jimmunol.147.3.921 . 1861080 . free .
• Brandt E, Van Damme J, Flad HD . 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 . July 1991 . 1873479 . 10.1016/1043-4666(91)90499-4 .
• Kargi HA, Campbell EJ, Kuhn C . 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 . August 1990 . 2164060 . 10.1177/38.8.2164060 . free .
• Pratt CW, Tobin RB, Church FC . Interaction of heparin cofactor II with neutrophil elastase and cathepsin G . The Journal of Biological Chemistry . 265 . 11 . 6092–7 . April 1990 . 10.1016/S0021-9258(19)39296-8 . 2318847 . free .
• Gabay JE, Scott RW, Campanelli D, Griffith J, Wilde C, Marra MN, Seeger M, Nathan CF . Antibiotic proteins of human polymorphonuclear leukocytes . Proceedings of the National Academy of Sciences of the United States of America . 86 . 14 . 5610–4 . July 1989 . 2501794 . 297672 . 10.1073/pnas.86.14.5610 . 1989PNAS...86.5610G . free .
• Hohn PA, Popescu NC, Hanson RD, Salvesen G, Ley TJ . Genomic organization and chromosomal localization of the human cathepsin G gene . The Journal of Biological Chemistry . 264 . 23 . 13412–9 . August 1989 . 10.1016/S0021-9258(18)80012-6 . 2569462 . free .
• Livesey SA, Buescher ES, Krannig GL, Harrison DS, Linner JG, Chiovetti R . Human neutrophil granule heterogeneity: immunolocalization studies using cryofixed, dried and embedded specimens . Scanning Microscopy. Supplement . 3 . 231–9; discussion 239–40 . 1989 . 2616953 .
• Campbell EJ, Silverman EK, Campbell MA . 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 . November 1989 . 10.4049/jimmunol.143.9.2961 . 2681419 . free .
• 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 . 8 . 2289–93 . April 1987 . 3304423 . 10.1021/bi00382a032 .
• Heck LW, Rostand KS, Hunter FA, Bhown A . Isolation, characterization, and amino-terminal amino acid sequence analysis of human neutrophil cathepsin G from normal donors . Analytical Biochemistry . 158 . 1 . 217–27 . October 1986 . 3799965 . 10.1016/0003-2697(86)90612-3 .
• Crocker J, Jenkins R, Burnett D . Immunohistochemical localization of cathepsin G in human tissues . The American Journal of Surgical Pathology . 9 . 5 . 338–43 . May 1985 . 3911778 . 10.1097/00000478-198505000-00003 . 23124253 .
• Klickstein LB, Kaempfer CE, Wintroub BU . The granulocyte-angiotensin system. Angiotensin I-converting activity of cathepsin G . The Journal of Biological Chemistry . 257 . 24 . 15042–6 . December 1982 . 10.1016/S0021-9258(18)33390-8 . 6294088 . free .
• LaRosa CA, Rohrer MJ, Benoit SE, Barnard MR, Michelson AD . 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 . July 1994 . 7517206 . 10.1182/blood.V84.1.158.158. free .
• Owen CA, Campbell MA, Sannes PL, Boukedes SS, Campbell EJ . Cell surface-bound elastase and cathepsin G on human neutrophils: a novel, non-oxidative mechanism by which neutrophils focus and preserve catalytic activity of serine proteinases . The Journal of Cell Biology . 131 . 3 . 775–89 . November 1995 . 7593196 . 2120617 . 10.1083/jcb.131.3.775 .
• Savage MJ, Iqbal M, Loh T, Trusko SP, Scott R, Siman R . Cathepsin G: localization in human cerebral cortex and generation of amyloidogenic fragments from the beta-amyloid precursor protein . Neuroscience . 60 . 3 . 607–19 . June 1994 . 7936190 . 10.1016/0306-4522(94)90490-1 . 24998185 .
• Grisolano JL, Sclar GM, Ley TJ . Early myeloid cell-specific expression of the human cathepsin G gene in transgenic mice . Proceedings of the National Academy of Sciences of the United States of America . 91 . 19 . 8989–93 . September 1994 . 8090757 . 44732 . 10.1073/pnas.91.19.8989 . 1994PNAS...91.8989G . free .
• Maruyama K, Sugano S . Oligo-capping: a simple method to replace the cap structure of eukaryotic mRNAs with oligoribonucleotides . Gene . 138 . 1–2 . 171–4 . January 1994 . 8125298 . 10.1016/0378-1119(94)90802-8 .

External links

• The MEROPS online database for peptidases and their inhibitors: S01.133

Notes and References

1. Janoff A, Scherer J . Mediators of inflammation in leukocyte lysosomes. IX. Elastinolytic activity in granules of human polymorphonuclear leukocytes . The Journal of Experimental Medicine . 128 . 5 . 1137–55 . November 1968 . 5303065 . 10.1084/jem.128.5.1137 . 2138566.
2. Kao RC, Wehner NG, Skubitz KM, Gray BH, Hoidal JR . Proteinase 3. A distinct human polymorphonuclear leukocyte proteinase that produces emphysema in hamsters . The Journal of Clinical Investigation . 82 . 6 . 1963–73 . December 1988 . 3198760 . 10.1172/JCI113816 . 442778.
3. Virca GD, Metz G, Schnebli HP . Similarities between human and rat leukocyte elastase and cathepsin G . European Journal of Biochemistry . 144 . 1 . 1–9 . October 1984 . 6566611 . 10.1111/j.1432-1033.1984.tb08423.x. free .
4. 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 . Characterization of polymorphic structure of cathepsin G gene: role in cardiovascular and cerebrovascular diseases . Arteriosclerosis, Thrombosis, and Vascular Biology . 21 . 9 . 1538–43 . September 2001 . 11557685 . 10.1161/hq0901.095555. free .
5. Salvesen G, Enghild JJ . 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 . 1991 . 1801740 .
6. 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 . 8 . 2289–93 . April 1987 . 3304423 . 10.1021/bi00382a032.
7. Korkmaz B, Moreau T, Gauthier F . Neutrophil elastase, proteinase 3 and cathepsin G: physicochemical properties, activity and physiopathological functions . Biochimie . 90 . 2 . 227–42 . February 2008 . 18021746 . 10.1016/j.biochi.2007.10.009 .
8. Thomas MP, Whangbo J, McCrossan G, Deutsch AJ, Martinod K, Walch M, Lieberman J . Leukocyte protease binding to nucleic acids promotes nuclear localization and cleavage of nucleic acid binding proteins . Journal of Immunology . 192 . 11 . 5390–7 . June 2014 . 24771851 . 4041364 . 10.4049/jimmunol.1303296 .
9. Pham CT . Neutrophil serine proteases: specific regulators of inflammation . Nature Reviews. Immunology . 6 . 7 . 541–50 . July 2006 . 16799473 . 10.1038/nri1841 . 111538 .
10. Web site: Entrez Gene: CTSG cathepsin G.
11. Shafer WM, Pohl J, Onunka VC, Bangalore N, Travis J . Human lysosomal cathepsin G and granzyme B share a functionally conserved broad spectrum antibacterial peptide . The Journal of Biological Chemistry . 266 . 1 . 112–6 . January 1991 . 10.1016/S0021-9258(18)52409-1 . 1985886 . free .
12. Beaufort N, Leduc D, Rousselle JC, Magdolen V, Luther T, Namane A, Chignard M, Pidard D . Proteolytic regulation of the urokinase receptor/CD87 on monocytic cells by neutrophil elastase and cathepsin G . Journal of Immunology . 172 . 1 . 540–9 . January 2004 . 14688365 . 10.4049/jimmunol.172.1.540. free .
13. Bank U, Ansorge S . More than destructive: neutrophil-derived serine proteases in cytokine bioactivity control . Journal of Leukocyte Biology . 69 . 2 . 197–206 . February 2001 . 10.1189/jlb.69.2.197 . 11272269 . 30791872 .
14. Reilly CF, Tewksbury DA, Schechter NM, Travis J . Rapid conversion of angiotensin I to angiotensin II by neutrophil and mast cell proteinases . The Journal of Biological Chemistry . 257 . 15 . 8619–22 . August 1982 . 10.1016/S0021-9258(18)34171-1 . 6807977 . free .
15. Sambrano GR, Huang W, Faruqi T, Mahrus S, Craik C, Coughlin SR . Cathepsin G activates protease-activated receptor-4 in human platelets . The Journal of Biological Chemistry . 275 . 10 . 6819–23 . March 2000 . 10702240 . 10.1074/jbc.275.10.6819. free .
16. Nadel JA . Role of mast cell and neutrophil proteases in airway secretion . The American Review of Respiratory Disease . 144 . 3 Pt 2 . S48–51 . September 1991 . 1892327 . 10.1164/ajrccm/144.3_pt_2.S48 .
17. Armao D, Kornfeld M, Estrada EY, Grossetete M, Rosenberg GA . Neutral proteases and disruption of the blood-brain barrier in rat . Brain Research . 767 . 2 . 259–64 . September 1997 . 9367256 . 10.1016/S0006-8993(97)00567-2 . 40103486 .
18. Szekanecz Z, Koch AE . Macrophages and their products in rheumatoid arthritis . Current Opinion in Rheumatology . 19 . 3 . 289–95 . May 2007 . 17414958 . 10.1097/BOR.0b013e32805e87ae . 8096646 .
19. Takei T, Sakai S, Yokonuma T, Ijima H, Kawakami K . Fabrication of artificial endothelialized tubes with predetermined three-dimensional configuration from flexible cell-enclosing alginate fibers . Biotechnology Progress . 23 . 1 . 182–6 . Jan–Feb 2007 . 17269686 . 10.1021/bp060152j . 40332839 .
20. Liu R, Chen L, Wu W, Chen H, Zhang S . Neutrophil serine proteases and their endogenous inhibitors in coronary artery ectasia patients . . 16 . 1 . 23–8 . January 2016 . 26467359 . 10.5152/akd.2015.6072 . 5336701 .
21. Komine K, Kuroishi T, Ozawa A, Komine Y, Minami T, Shimauchi H, Sugawara S . Cleaved inflammatory lactoferrin peptides in parotid saliva of periodontitis patients . Molecular Immunology . 44 . 7 . 1498–508 . March 2007 . 17030385 . 10.1016/j.molimm.2006.09.003 .
22. Shimoda N, Fukazawa N, Nonomura K, Fairchild RL . Cathepsin g is required for sustained inflammation and tissue injury after reperfusion of ischemic kidneys . The American Journal of Pathology . 170 . 3 . 930–40 . March 2007 . 17322378 . 10.2353/ajpath.2007.060486 . 1864870.
23. Kawabata K, Hagio T, Matsuoka S . The role of neutrophil elastase in acute lung injury . European Journal of Pharmacology . 451 . 1 . 1–10 . September 2002 . 12223222 . 10.1016/s0014-2999(02)02182-9.
24. Moraes TJ, Chow CW, Downey GP . Proteases and lung injury . Critical Care Medicine . 31 . 4 Suppl . S189–94 . April 2003 . 12682439 . 10.1097/01.CCM.0000057842.90746.1E . 45296600 .
25. Twigg MS, Brockbank S, Lowry P, FitzGerald SP, Taggart C, Weldon S . The Role of Serine Proteases and Antiproteases in the Cystic Fibrosis Lung . Mediators of Inflammation . 2015 . 2015 . 293053 . 26185359 . 10.1155/2015/293053 . 4491392. free .
26. 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 . Up-regulation of Cathepsin G in the Development of Chronic Postsurgical Pain: An Experimental and Clinical Genetic Study . Anesthesiology . 123 . 4 . 838–50 . October 2015 . 26270939 . 10.1097/ALN.0000000000000828 . 43571196 .
27. Whitelock RB, Fukuchi T, Zhou L, Twining SS, Sugar J, Feder RS, Yue BY . Cathepsin G, acid phosphatase, and alpha 1-proteinase inhibitor messenger RNA levels in keratoconus corneas . Investigative Ophthalmology & Visual Science . 38 . 2 . 529–34 . February 1997 . 9040486 .
28. Baumann M, Pham CT, Benarafa C . SerpinB1 is critical for neutrophil survival through cell-autonomous inhibition of cathepsin G . Blood . 121 . 19 . 3900–7, S1–6 . May 2013 . 23532733 . 10.1182/blood-2012-09-455022 . 3650706.
29. Son ED, Shim JH, Choi H, Kim H, Lim KM, Chung JH, Byun SY, Lee TR . Cathepsin G inhibitor prevents ultraviolet B-induced photoaging in hairless mice via inhibition of fibronectin fragmentation . Dermatology . 224 . 4 . 352–60 . 2012 . 22759782 . 10.1159/000339337 . 29489606 .
30. Cruz-Silva I, Neuhof C, Gozzo AJ, Nunes VA, Hirata IY, Sampaio MU, Figueiredo-Ribeiro Rde C, Neuhof H, Araújo Mda S . 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 . December 2013 . 24140156 . 10.1016/j.phytochem.2013.09.025 . 2013PChem..96..235C .
31. Craciun I, Fenner AM, Kerns RJ . N-Arylacyl O-sulfonated aminoglycosides as novel inhibitors of human neutrophil elastase, cathepsin G and proteinase 3 . Glycobiology . February 2016 . 26850997 . 10.1093/glycob/cww011 . 26 . 7 . 701–9. 4976519 .
32. Wang J, Sjöberg S, Tang TT, Oörni K, Wu W, Liu C, Secco B, Tia V, Sukhova GK, Fernandes C, Lesner A, Kovanen PT, Libby P, Cheng X, Shi GP . Cathepsin G activity lowers plasma LDL and reduces atherosclerosis . Biochimica et Biophysica Acta (BBA) - Molecular Basis of Disease . 1842 . 11 . 2174–83 . November 2014 . 25092171 . 10.1016/j.bbadis.2014.07.026 . 4188792.