Cathepsin G

CTSG
Available structures PDB Ortholog search: PDBe RCSB List of PDB id codes 1AU8, 1CGH, 1KYN, 1T32
Identifiers
Aliases	CTSG , CATG, CG, cathepsin G
External IDs	OMIM: 116830; MGI: 88563; HomoloGene: 105646; GeneCards: CTSG; OMA:CTSG - orthologs
Gene location (Human) Chr. Chromosome 14 (human) [1] Band 14q12 Start 24,573,518 bp [1] End 24,576,250 bp [1]
Gene location (Mouse) Chr. Chromosome 14 (mouse) [2] Band 14 C3|14 28.19 cM Start 56,337,338 bp [2] End 56,340,031 bp [2]
RNA expression pattern Bgee Human Mouse (ortholog) Top expressed in trabecular bone bone marrow cells triceps brachii muscle gallbladder skin of hip testicle monocyte skin of leg skin of abdomen rectum Top expressed in tibiofemoral joint fetal liver hematopoietic progenitor cell granulocyte gastrula bone marrow decidua ankle joint body of femur spleen vestibular membrane of cochlear duct More reference expression data BioGPS More reference expression data
Gene ontology Molecular function heparin binding peptidase activity protein binding hydrolase activity serine-type endopeptidase activity serine-type peptidase activity Cellular component extracellular matrix plasma membrane secretory granule cell surface extracellular exosome nucleus extracellular space azurophil granule lumen cytoplasmic stress granule extracellular region cytoplasm collagen-containing extracellular matrix Biological process extracellular matrix disassembly proteolysis angiotensin maturation protein phosphorylation response to lipopolysaccharide positive regulation of immune response defense response to bacterium immune response defense response to Gram-positive bacterium antimicrobial humoral response neutrophil degranulation defense response to fungus neutrophil-mediated killing of gram-positive bacterium Sources:Amigo / QuickGO
Orthologs Species Human Mouse Entrez 1511 13035 Ensembl ENSG00000100448 ENSMUSG00000040314 UniProt P08311 P28293 RefSeq (mRNA) NM_001911 NM_007800 RefSeq (protein) NP_001902 NP_031826 Location (UCSC) Chr 14: 24.57 – 24.58 Mb Chr 14: 56.34 – 56.34 Mb PubMed search [3] [4]
Wikidata
View/Edit Human View/Edit Mouse

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. ^{[5] [6] [7] [8]}

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. ^[9] Cathepsin G homologs evolved from a common ancestor via gene duplication. ^[10]

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. ^[11] 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. ^[12]

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. ^[13] 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. ^[14] It localizes to Neutrophil extracellular traps (NETs), via its high affinity for DNA, an unusual property for serine proteases. ^[13] Transcript variants utilizing alternative polyadenylation signals exist for this gene. ^[15] Cathepsin G was also found to exert broad-spectrum antibacterial action against Gram-negative and –positive bacteria independent of the function mentioned above. ^[16] 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. ^{[17] [18] [19] [20] [21]} Potential implications of the enzyme in blood-brain barrier breakdown was also found. ^[22]

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. ^{[23] [24] [25] [26] [27]} It is also implicated in a variety of infectious inflammatory diseases, including chronic obstructive pulmonary disease, acute respiratory distress syndrome, and cystic fibrosis. ^{[28] [29] [30]} 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. ^[31] An upregulation of cathepsin G was reported in studies of keratoconus. ^[32]

Interactions

Cathepsin G has been found to interact with:

• SERPINB1 ^[33]

Cathepsin G is inhibited by:

• [2-[3-[[(1-benzoyl-4-piperidinyl)methylamino]carbonyl]-2-naphthalenyl]-1-(1-naphthalenyl)-2-oxoethyl]-phosphonic acid (KPA) ^[34]
• Caesalpinia echinata elastase inhibitor ^[35]
• N-Arylacyl O-sulfonated aminoglycosides ^[36]

Cathepsin G lowers levels of:

• Low-density lipoprotein ^[37]

See also

• Cathepsins

References

1. GRCh38: Ensembl release 89: ENSG00000100448 – Ensembl, May 2017
2. GRCm38: Ensembl release 89: ENSMUSG00000040314 – Ensembl, May 2017
3. "Human PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
4. "Mouse PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
5. Janoff A, Scherer J (November 1968). "Mediators of inflammation in leukocyte lysosomes. IX. Elastinolytic activity in granules of human polymorphonuclear leukocytes". The Journal of Experimental Medicine. 128 (5): 1137–55. doi:10.1084/jem.128.5.1137. PMC   2138566 . PMID   5303065.
6. Kao RC, Wehner NG, Skubitz KM, Gray BH, Hoidal JR (December 1988). "Proteinase 3. A distinct human polymorphonuclear leukocyte proteinase that produces emphysema in hamsters". The Journal of Clinical Investigation. 82 (6): 1963–73. doi:10.1172/JCI113816. PMC   442778 . PMID   3198760.
7. 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". In Evered D, Whelan J (eds.). Ciba Foundation Symposium 75 - Protein Degradation in Health and Disease. Novartis Foundation Symposia. Vol. 75. pp. 105–21. doi:10.1002/9780470720585.ch7. ISBN   9780470720585. PMID   399884.
8. Virca GD, Metz G, Schnebli HP (October 1984). "Similarities between human and rat leukocyte elastase and cathepsin G". European Journal of Biochemistry. 144 (1): 1–9. doi: 10.1111/j.1432-1033.1984.tb08423.x . PMID   6566611.
9. 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 . PMID   11557685.
10. 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. PMID   1801740.
11. 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. PMID   3304423.
12. 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. PMID   18021746.
13. Thomas MP, Whangbo J, McCrossan G, Deutsch AJ, Martinod K, Walch M, Lieberman J (June 2014). "Leukocyte protease binding to nucleic acids promotes nuclear localization and cleavage of nucleic acid binding proteins". Journal of Immunology. 192 (11): 5390–7. doi:10.4049/jimmunol.1303296. PMC   4041364 . PMID   24771851.
14. Pham CT (July 2006). "Neutrophil serine proteases: specific regulators of inflammation". Nature Reviews. Immunology. 6 (7): 541–50. doi:10.1038/nri1841. PMID   16799473. S2CID   111538.
15. "Entrez Gene: CTSG cathepsin G".
16. 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. doi: 10.1016/S0021-9258(18)52409-1 . PMID   1985886.
17. 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 . PMID   14688365.
18. 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. doi:10.1189/jlb.69.2.197. PMID   11272269. S2CID   30791872.
19. 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. doi: 10.1016/S0021-9258(18)34171-1 . PMID   6807977.
20. 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 . PMID   10702240.
21. 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. PMID   1892327.
22. 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. PMID   9367256. S2CID   40103486.
23. 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. hdl: 2437/89141 . PMID   17414958. S2CID   8096646.
24. 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. PMID   17269686. S2CID   40332839.
25. Liu R, Chen L, Wu W, Chen H, Zhang S (January 2016). "Neutrophil serine proteases and their endogenous inhibitors in coronary artery ectasia patients". Anatolian Journal of Cardiology . 16 (1): 23–8. doi:10.5152/akd.2015.6072. PMC   5336701 . PMID   26467359.
26. Komine K, Kuroishi T, Ozawa A, Komine Y, Minami T, Shimauchi H, Sugawara S (March 2007). "Cleaved inflammatory lactoferrin peptides in parotid saliva of periodontitis patients". Molecular Immunology. 44 (7): 1498–508. doi:10.1016/j.molimm.2006.09.003. PMID   17030385.
27. Shimoda N, Fukazawa N, Nonomura K, Fairchild RL (March 2007). "Cathepsin g is required for sustained inflammation and tissue injury after reperfusion of ischemic kidneys". The American Journal of Pathology. 170 (3): 930–40. doi:10.2353/ajpath.2007.060486. PMC   1864870 . PMID   17322378.
28. 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. PMID   12223222.
29. Moraes TJ, Chow CW, Downey GP (April 2003). "Proteases and lung injury". Critical Care Medicine. 31 (4 Suppl): S189–94. doi:10.1097/01.CCM.0000057842.90746.1E. PMID   12682439. S2CID   45296600.
30. Twigg MS, Brockbank S, Lowry P, FitzGerald SP, Taggart C, Weldon S (2015). "The Role of Serine Proteases and Antiproteases in the Cystic Fibrosis Lung". Mediators of Inflammation. 2015: 293053. doi: 10.1155/2015/293053 . PMC   4491392 . PMID   26185359.
31. 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. PMID   26270939. S2CID   43571196.
32. Whitelock RB, Fukuchi T, Zhou L, Twining SS, Sugar J, Feder RS, Yue BY (February 1997). "Cathepsin G, acid phosphatase, and alpha 1-proteinase inhibitor messenger RNA levels in keratoconus corneas". Investigative Ophthalmology & Visual Science. 38 (2): 529–34. PMID   9040486.
33. Baumann M, Pham CT, Benarafa C (May 2013). "SerpinB1 is critical for neutrophil survival through cell-autonomous inhibition of cathepsin G". Blood. 121 (19): 3900–7, S1–6. doi:10.1182/blood-2012-09-455022. PMC   3650706 . PMID   23532733.
34. 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. PMID   22759782. S2CID   29489606.
35. 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. Bibcode:2013PChem..96..235C. doi:10.1016/j.phytochem.2013.09.025. PMID   24140156.
36. 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 (7): 701–9. doi:10.1093/glycob/cww011. PMC   4976519 . PMID   26850997.
37. 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 (November 2014). "Cathepsin G activity lowers plasma LDL and reduces atherosclerosis". Biochimica et Biophysica Acta (BBA) - Molecular Basis of Disease. 1842 (11): 2174–83. doi:10.1016/j.bbadis.2014.07.026. PMC   4188792 . PMID   25092171.

Further reading

• 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. PMID   11945165.
• 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. doi:10.1152/ajplung.1992.263.2.L249. PMID   1387511.
• 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. PMID   1452887. S2CID   27658837.
• 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. doi: 10.4049/jimmunol.147.3.921 . PMID   1861080.
• 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. PMID   1873479.
• 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 . PMID   2164060.
• 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. doi: 10.1016/S0021-9258(19)39296-8 . PMID   2318847.
• Gabay JE, Scott RW, Campanelli D, Griffith J, Wilde C, Marra MN, Seeger M, Nathan CF (July 1989). "Antibiotic proteins of human polymorphonuclear leukocytes". Proceedings of the National Academy of Sciences of the United States of America. 86 (14): 5610–4. Bibcode:1989PNAS...86.5610G. doi: 10.1073/pnas.86.14.5610 . PMC   297672 . PMID   2501794.
• 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. doi: 10.1016/S0021-9258(18)80012-6 . PMID   2569462.
• 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. PMID   2616953.
• 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. doi: 10.4049/jimmunol.143.9.2961 . PMID   2681419.
• 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. PMID   3304423.
• 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. PMID   3799965.
• 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. PMID   3911778. S2CID   23124253.
• 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. doi: 10.1016/S0021-9258(18)33390-8 . PMID   6294088.
• 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. doi: 10.1182/blood.V84.1.158.158 . PMID   7517206.
• Owen CA, Campbell MA, Sannes PL, Boukedes SS, Campbell EJ (November 1995). "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. doi:10.1083/jcb.131.3.775. PMC   2120617 . PMID   7593196.
• 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. PMID   7936190. S2CID   24998185.
• Grisolano JL, Sclar GM, Ley TJ (September 1994). "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. Bibcode:1994PNAS...91.8989G. doi: 10.1073/pnas.91.19.8989 . PMC   44732 . PMID   8090757.
• 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. PMID   8125298.

External links

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

This article incorporates text from the United States National Library of Medicine, which is in the public domain.