Cathepsin C
| Cathepsin C exclusion domain | |||||||
|---|---|---|---|---|---|---|---|
re-determination of the native structure of human dipeptidyl peptidase i (cathepsin c) | |||||||
| Identifiers | |||||||
| Symbol | CathepsinC_exc | ||||||
| Pfam | PF08773 | ||||||
| InterPro | IPR014882 | ||||||
| SCOP2 | 1k3b / SCOPe / SUPFAM | ||||||
| |||||||
Cathepsin C (CTSC) also known as dipeptidyl peptidase I (DPP-I or DPP1) is a lysosomal exo-cysteine protease belonging to the peptidase C1 protein family, a subgroup of the cysteine cathepsins. In humans, it is encoded by the CTSC gene.[5][6]
Function
Cathepsin C appears to be a central coordinator for activation of many serine proteases in immune/inflammatory cells.
Cathepsin C catalyses excision of dipeptides from the N-terminus of protein and peptide substrates, except if (i) the amino group of the N-terminus is blocked, (ii) the site of cleavage is on either side of a proline residue, (iii) the N-terminal residue is lysine or arginine, or (iv) the structure of the peptide or protein prevents further digestion from the N-terminus.
Inflammatory response
Particularly, it is involved in activation of neutrophil serine proteases (NSPs; i.e., cathepsin G, proteinase 3 and neutrophil elastase) as they are synthesised as inactive proenzymes during neutrophil maturation. Then, they are released during degranulation.[7][8] Other enzymes activated by cathepsin C are: chymase and tryptase in mast cells and granzymes A and B, cathepsin G, and elastase in lymphocytes and natural killer cells (NK cells).[9]
Overactivation of NSPs causes a cascade of processess that result in excessive lung inflammation and reduced pathogen clearance. They involve reduced secretion of antileukoproteinase, extracellular matrix degradation, activation of IL-1β, IL-8 and TNF-α as well as inhibition of alpha-1 antitrypsin, an enzyme involved in NSP degradation.[8]
Structure
The cDNAs encoding rat, human, murine, bovine, dog and two Schistosome cathepsin Cs have been cloned and sequenced and show that the enzyme is highly conserved.[10] The human and rat cathepsin C cDNAs encode precursors (prepro-cathepsin C) comprising signal peptides of 24 residues, pro-regions of 205 (rat cathepsin C) or 206 (human cathepsin C) residues and catalytic domains of 233 residues which contain the catalytic residues and are 30–40% identical to the mature amino acid sequences of papain and a number of other cathepsins including cathepsins, B, H, K, L, and S.[11]
The translated prepro-cathepsin C is processed into the mature form by at least four cleavages of the polypeptide chain. The signal peptide is removed during translocation or secretion of the pro-enzyme (pro-cathepsin C) and a large N-terminal proregion fragment (also known as the exclusion domain),[12] which is retained in the mature enzyme, is separated from the catalytic domain by excision of a minor C-terminal part of the pro-region, called the activation peptide. A heavy chain of about 164 residues and a light chain of about 69 residues are generated by cleavage of the catalytic domain.
Unlike the other members of the papain family, mature cathepsin C consists of four subunits, each composed of the N-terminal proregion fragment, the heavy chain and the light chain. Both the pro-region fragment and the heavy chain are glycosylated.
Clinical significance
Defects in the encoded protein have been shown to be a cause of Papillon-Lefevre disease,[13][14] an autosomal recessive disorder characterized by palmoplantar keratosis and periodontitis.
Inhibition of DPP-I addresses the inflammatory response that is thought to be responsible for one of many aspects of degenerative lung diseases, including bronchiectasis[15], chronic obstructive pulmonary disease (COPD), asthma and asthma-COPD overlap [16].
Brensocatib, a DPP-I inhibitor, was approved in 2025 by the FDA[17] and the EMA[18] to treat bronchiectasis.
References
- ^ a b c GRCh38: Ensembl release 89: ENSG00000109861 – Ensembl, May 2017
- ^ a b c GRCm38: Ensembl release 89: ENSMUSG00000030560 – Ensembl, May 2017
- ^ "Human PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
- ^ "Mouse PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
- ^ "Entrez Gene: CTSC cathepsin C".
- ^ Paris A, Strukelj B, Pungercar J, Renko M, Dolenc I, Turk V (August 1995). "Molecular cloning and sequence analysis of human preprocathepsin C". FEBS Letters. 369 (2–3): 326–330. Bibcode:1995FEBSL.369..326P. doi:10.1016/0014-5793(95)00777-7. PMID 7649281. S2CID 45737414.
- ^ Korkmaz B, Horwitz MS, Jenne DE, Gauthier F (December 2010). "Neutrophil elastase, proteinase 3, and cathepsin G as therapeutic targets in human diseases". Pharmacological Reviews. 62 (4): 726–759. doi:10.1124/pr.110.002733. PMC 2993259. PMID 21079042.
- ^ a b Chalmers JD, Kettritz R, Korkmaz B (2023-12-14). "Dipeptidyl peptidase 1 inhibition as a potential therapeutic approach in neutrophil-mediated inflammatory disease". Frontiers in Immunology. 14 1239151. doi:10.3389/fimmu.2023.1239151. PMC 10755895. PMID 38162644.
- ^ McGuire M, Lipsky P, Thiele D (February 1993). "Generation of active myeloid and lymphoid granule serine proteases requires processing by the granule thiol protease dipeptidyl peptidase I." Journal of Biological Chemistry. 268 (4): 2458–2467. doi:10.1016/S0021-9258(18)53798-4.
- ^ Hola-Jamriska L, Tort JF, Dalton JP, Day SR, Fan J, Aaskov J, et al. (August 1998). "Cathepsin C from Schistosoma japonicum--cDNA encoding the preproenzyme and its phylogenetic relationships". European Journal of Biochemistry. 255 (3): 527–534. doi:10.1046/j.1432-1327.1998.2550527.x. PMID 9738890.
- ^ Kominami E, Ishido K, Muno D, Sato N (July 1992). "The primary structure and tissue distribution of cathepsin C". Biological Chemistry Hoppe-Seyler. 373 (7): 367–373. doi:10.1515/bchm3.1992.373.2.367. PMID 1515062.
- ^ Turk D, Janjić V, Stern I, Podobnik M, Lamba D, Dahl SW, et al. (December 2001). "Structure of human dipeptidyl peptidase I (cathepsin C): exclusion domain added to an endopeptidase framework creates the machine for activation of granular serine proteases". The EMBO Journal. 20 (23): 6570–6582. doi:10.1093/emboj/20.23.6570. PMC 125750. PMID 11726493.
- ^ Wani AA, Devkar N, Patole MS, Shouche YS (February 2006). "Description of two new cathepsin C gene mutations in patients with Papillon-Lefèvre syndrome". Journal of Periodontology. 77 (2): 233–237. doi:10.1902/jop.2006.050124. PMID 16460249.
- ^ Meade JL, de Wynter EA, Brett P, Sharif SM, Woods CG, Markham AF, et al. (May 2006). "A family with Papillon-Lefevre syndrome reveals a requirement for cathepsin C in granzyme B activation and NK cell cytolytic activity". Blood. 107 (9): 3665–3668. doi:10.1182/blood-2005-03-1140. PMID 16410452.
- ^ Johnson E, Gilmour A, Chalmers JD (April 2025). "Dipeptidyl peptidase-1 inhibitors in bronchiectasis". European Respiratory Review. 34 (176): 240257. doi:10.1183/16000617.0257-2024. PMC 12175074. PMID 40533102.
- ^ Tanabe N, Matsumoto H, Kogo M, Morimoto C, Nomura N, Hayashi Y, et al. (May 2025). "Exploring the roles of airway dipeptidyl peptidase 1 in obstructive airway disease". ERJ Open Research. 11 (3): 00841–02024. doi:10.1183/23120541.00841-2024. PMC 12086829. PMID 40391061.
- ^ Research CF (2026-01-02). "Novel Drug Approvals for 2025". FDA.
- ^ "First treatment for serious chronic lung disease | European Medicines Agency (EMA)". www.ema.europa.eu. 2025-10-17. Retrieved 2026-01-10.
Further reading
- McGuire MJ, Lipsky PE, Thiele DL (June 1992). "Purification and characterization of dipeptidyl peptidase I from human spleen". Archives of Biochemistry and Biophysics. 295 (2): 280–288. doi:10.1016/0003-9861(92)90519-3. PMID 1586157.
- Paris A, Strukelj B, Pungercar J, Renko M, Dolenc I, Turk V (August 1995). "Molecular cloning and sequence analysis of human preprocathepsin C". FEBS Letters. 369 (2–3): 326–330. Bibcode:1995FEBSL.369..326P. doi:10.1016/0014-5793(95)00777-7. PMID 7649281. S2CID 45737414.
- Dolenc I, Turk B, Pungercic G, Ritonja A, Turk V (September 1995). "Oligomeric structure and substrate induced inhibition of human cathepsin C". The Journal of Biological Chemistry. 270 (37): 21626–21631. doi:10.1074/jbc.270.37.21626. PMID 7665576.
- 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): 171–174. doi:10.1016/0378-1119(94)90802-8. PMID 8125298.
- Rao NV, Rao GV, Hoidal JR (April 1997). "Human dipeptidyl-peptidase I. Gene characterization, localization, and expression". The Journal of Biological Chemistry. 272 (15): 10260–10265. doi:10.1074/jbc.272.15.10260. PMID 9092576.
- Fischer J, Blanchet-Bardon C, Prud'homme JF, Pavek S, Steijlen PM, Dubertret L, et al. (1997). "Mapping of Papillon-Lefevre syndrome to the chromosome 11q14 region". European Journal of Human Genetics. 5 (3): 156–160. doi:10.1159/000484751. hdl:2066/24363. PMID 9272739.
- Suzuki Y, Yoshitomo-Nakagawa K, Maruyama K, Suyama A, Sugano S (October 1997). "Construction and characterization of a full length-enriched and a 5'-end-enriched cDNA library". Gene. 200 (1–2): 149–156. doi:10.1016/S0378-1119(97)00411-3. PMID 9373149.
- Cigić B, Krizaj I, Kralj B, Turk V, Pain RH (January 1998). "Stoichiometry and heterogeneity of the pro-region chain in tetrameric human cathepsin C". Biochimica et Biophysica Acta (BBA) - Protein Structure and Molecular Enzymology. 1382 (1): 143–150. doi:10.1016/S0167-4838(97)00173-8. PMID 9507095.
- Toomes C, James J, Wood AJ, Wu CL, McCormick D, Lench N, et al. (December 1999). "Loss-of-function mutations in the cathepsin C gene result in periodontal disease and palmoplantar keratosis". Nature Genetics. 23 (4): 421–424. doi:10.1038/70525. PMID 10581027. S2CID 11433166.
- Hart TC, Hart PS, Bowden DW, Michalec MD, Callison SA, Walker SJ, et al. (December 1999). "Mutations of the cathepsin C gene are responsible for Papillon-Lefèvre syndrome". Journal of Medical Genetics. 36 (12): 881–887. doi:10.1136/jmg.36.12.881. PMC 1734286. PMID 10593994.
- Hart TC, Hart PS, Michalec MD, Zhang Y, Firatli E, Van Dyke TE, et al. (February 2000). "Haim-Munk syndrome and Papillon-Lefèvre syndrome are allelic mutations in cathepsin C". Journal of Medical Genetics. 37 (2): 88–94. doi:10.1136/jmg.37.2.88. PMC 1734521. PMID 10662807.
- Hart TC, Hart PS, Michalec MD, Zhang Y, Marazita ML, Cooper M, et al. (February 2000). "Localisation of a gene for prepubertal periodontitis to chromosome 11q14 and identification of a cathepsin C gene mutation". Journal of Medical Genetics. 37 (2): 95–101. doi:10.1136/jmg.37.2.95. PMC 1734516. PMID 10662808.
- Suzuki Y, Ishihara D, Sasaki M, Nakagawa H, Hata H, Tsunoda T, et al. (March 2000). "Statistical analysis of the 5' untranslated region of human mRNA using "Oligo-Capped" cDNA libraries". Genomics. 64 (3): 286–297. doi:10.1006/geno.2000.6076. PMID 10756096.
- Cigić B, Dahl SW, Pain RH (October 2000). "The residual pro-part of cathepsin C fulfills the criteria required for an intramolecular chaperone in folding and stabilizing the human proenzyme". Biochemistry. 39 (40): 12382–12390. doi:10.1021/bi0008837. PMID 11015218.
- Hartley JL, Temple GF, Brasch MA (November 2000). "DNA cloning using in vitro site-specific recombination". Genome Research. 10 (11): 1788–1795. doi:10.1101/gr.143000. PMC 310948. PMID 11076863.
- Hart PS, Zhang Y, Firatli E, Uygur C, Lotfazar M, Michalec MD, et al. (December 2000). "Identification of cathepsin C mutations in ethnically diverse papillon-Lefèvre syndrome patients". Journal of Medical Genetics. 37 (12): 927–932. doi:10.1136/jmg.37.12.927. PMC 1734492. PMID 11106356.
- Zhang Y, Lundgren T, Renvert S, Tatakis DN, Firatli E, Uygur C, et al. (February 2001). "Evidence of a founder effect for four cathepsin C gene mutations in Papillon-Lefèvre syndrome patients". Journal of Medical Genetics. 38 (2): 96–101. doi:10.1136/jmg.38.2.96. PMC 1734811. PMID 11158173.
- Nakano A, Nomura K, Nakano H, Ono Y, LaForgia S, Pulkkinen L, et al. (February 2001). "Papillon-Lefèvre syndrome: mutations and polymorphisms in the cathepsin C gene". The Journal of Investigative Dermatology. 116 (2): 339–343. doi:10.1046/j.1523-1747.2001.01244.x. PMID 11180012.
- Allende LM, García-Pérez MA, Moreno A, Corell A, Carasol M, Martínez-Canut P, et al. (February 2001). "Cathepsin C gene: First compound heterozygous patient with Papillon-Lefèvre syndrome and a novel symptomless mutation". Human Mutation. 17 (2): 152–153. doi:10.1002/1098-1004(200102)17:2<152::AID-HUMU10>3.0.CO;2-#. PMID 11180601. S2CID 196603893.
- Wiemann S, Weil B, Wellenreuther R, Gassenhuber J, Glassl S, Ansorge W, et al. (March 2001). "Toward a catalog of human genes and proteins: sequencing and analysis of 500 novel complete protein coding human cDNAs". Genome Research. 11 (3): 422–435. doi:10.1101/gr.GR1547R. PMC 311072. PMID 11230166.
External links
- The MEROPS online database for peptidases and their inhibitors: C01.070 Archived 2015-12-22 at the Wayback Machine
- Cathepsin+C at the U.S. National Library of Medicine Medical Subject Headings (MeSH)