Biology:Cathepsin C

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Cathepsin C exclusion domain
re-determination of the native structure of human dipeptidyl peptidase i (cathepsin c)
Identifiers
SymbolCathepsinC_exc
PfamPF08773
InterProIPR014882
SCOP21k3b / 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.[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". https://www.ncbi.nlm.nih.gov/gene?Db=gene&Cmd=ShowDetailView&TermToSearch=1075. 
  2. ↑ "Molecular cloning and sequence analysis of human preprocathepsin C". FEBS Letters 369 (2–3): 326–330. August 1995. doi:10.1016/0014-5793(95)00777-7. PMID 7649281. Bibcode: 1995FEBSL.369..326P. 
  3. ↑ "Neutrophil elastase, proteinase 3, and cathepsin G as therapeutic targets in human diseases". Pharmacological Reviews 62 (4): 726–759. December 2010. doi:10.1124/pr.110.002733. PMID 21079042. 
  4. ↑ 4.0 4.1 "Dipeptidyl peptidase 1 inhibition as a potential therapeutic approach in neutrophil-mediated inflammatory disease". Frontiers in Immunology 14. 2023-12-14. doi:10.3389/fimmu.2023.1239151. PMID 38162644. 
  5. ↑ "Generation of active myeloid and lymphoid granule serine proteases requires processing by the granule thiol protease dipeptidyl peptidase I." (in en). Journal of Biological Chemistry 268 (4): 2458–2467. February 1993. doi:10.1016/S0021-9258(18)53798-4. 
  6. ↑ "Cathepsin C from Schistosoma japonicum--cDNA encoding the preproenzyme and its phylogenetic relationships". European Journal of Biochemistry 255 (3): 527–534. August 1998. doi:10.1046/j.1432-1327.1998.2550527.x. PMID 9738890. 
  7. ↑ "The primary structure and tissue distribution of cathepsin C". Biological Chemistry Hoppe-Seyler 373 (7): 367–373. July 1992. doi:10.1515/bchm3.1992.373.2.367. PMID 1515062. 
  8. ↑ "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. December 2001. doi:10.1093/emboj/20.23.6570. PMID 11726493. 
  9. ↑ "Description of two new cathepsin C gene mutations in patients with Papillon-Lefèvre syndrome". Journal of Periodontology 77 (2): 233–237. February 2006. doi:10.1902/jop.2006.050124. PMID 16460249. 
  10. ↑ "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. May 2006. doi:10.1182/blood-2005-03-1140. PMID 16410452. 
  11. ↑ "Dipeptidyl peptidase-1 inhibitors in bronchiectasis". European Respiratory Review 34 (176): 240257. April 2025. doi:10.1183/16000617.0257-2024. PMID 40533102. 
  12. ↑ "Exploring the roles of airway dipeptidyl peptidase 1 in obstructive airway disease". ERJ Open Research 11 (3): 00841–02024. May 2025. doi:10.1183/23120541.00841-2024. PMID 40391061. 
  13. ↑ "Novel Drug Approvals for 2025" (in en). FDA. 2026-01-02. https://www.fda.gov/drugs/novel-drug-approvals-fda/novel-drug-approvals-2025. 
  14. ↑ "First treatment for serious chronic lung disease | European Medicines Agency (EMA)" (in en). 2025-10-17. https://www.ema.europa.eu/en/news/first-treatment-serious-chronic-lung-disease. 

Further reading



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