Cathepsin C exclusion domain
PfamPF08773
InterproIPR014882
Scop1k3b

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.[1][2]

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.[3][4] 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).[5]

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.[4]

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.[6] 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.[7]

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),[8] 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,[9][10] 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[11], chronic obstructive pulmonary disease (COPD), asthma and asthma-COPD overlap [12].

Brensocatib, a DPP-I inhibitor, was approved in 2025 by the FDA[13] and the EMA[14] to treat bronchiectasis.

References

  1. ^ "Entrez Gene: CTSC cathepsin C"
  2. ^ 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
  3. ^ 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
  4. ^ 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. doi:10.3389/fimmu.2023.1239151. PMC 10755895. PMID 38162644
  5. ^ 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
  6. ^ Hola-Jamriska L, Tort JF, Dalton JP, Day SR, Fan J, Aaskov J, Brindley PJ (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
  7. ^ 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
  8. ^ Turk D, Janjić V, Stern I, Podobnik M, Lamba D, Dahl SW, Lauritzen C, Pedersen J, Turk V, Turk B (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
  9. ^ 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
  10. ^ Meade JL, de Wynter EA, Brett P, Sharif SM, Woods CG, Markham AF, Cook GP (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
  11. ^ 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
  12. ^ Tanabe N, Matsumoto H, Kogo M, Morimoto C, Nomura N, Hayashi Y, Sakamoto R, Oguma T, Nagasaki T, Sunadome H, Sato A, Sato S, Ohashi K, Tsukahara T, Hirai T (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
  13. ^ Research CF (2026-01-02). "Novel Drug Approvals for 2025". FDA
  14. ^ "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, Weissenbach J (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, Hewitt C, Moynihan L, Roberts E, Woods CG, Markham A, Wong M, Widmer R, Ghaffar KA, Pemberton M, Hussein IR, Temtamy SA, Davies R, Read AP, Sloan P, Dixon MJ, Thakker NS (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, Zhang Y, Firatli E (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, Stabholz A, Zlotogorski A, Shapira L, Soskolne WA (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, Yassin OM, Nusier M, Walker S (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, Watanabe M, Komatsu T, Ota T, Isogai T, Suyama A, Sugano S (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, Marks JJ, Lu X, Coates BJ, Seow WK, Marshall R, Williams D, Reed JB, Wright JT, Hart TC (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, Hart PS, Gorry MC, Marks JJ, Hart TC (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, Hashimoto I, Uitto J (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, Arnaiz-Villena A (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, Böcher M, Blöcker H, Bauersachs S, Blum H, Lauber J, Düsterhöft A, Beyer A, Köhrer K, Strack N, Mewes HW, Ottenwälder B, Obermaier B, Tampe J, Heubner D, Wambutt R, Korn B, Klein M, Poustka A (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
  • The MEROPS online database for peptidases and their inhibitors: C01.070 Archived 2015-12-22 at the Wayback Machine