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CTSC

Official Full Name
cathepsin C
Organism
Homo sapiens
GeneID
1075
Background
This gene encodes a member of the peptidase C1 family and lysosomal cysteine proteinase that appears to be a central coordinator for activation of many serine proteinases in cells of the immune system. Alternative splicing results in multiple transcript variants, at least one of which encodes a preproprotein that is proteolytically processed to generate heavy and light chains that form a disulfide-linked dimer. A portion of the propeptide acts as an intramolecular chaperone for the folding and stabilization of the mature enzyme. This enzyme requires chloride ions for activity and can degrade glucagon. Defects in the encoded protein have been shown to be a cause of Papillon-Lefevre syndrome, an autosomal recessive disorder characterized by palmoplantar keratosis and periodontitis. [provided by RefSeq, Nov 2015]
Synonyms
JP; HMS; JPD; PLS; CPPI; DPP1; DPPI; PALS; DPP-I; PDON1;
Bio Chemical Class
Peptidase
Protein Sequence
MGAGPSLLLAALLLLLSGDGAVRCDTPANCTYLDLLGTWVFQVGSSGSQRDVNCSVMGPQEKKVVVYLQKLDTAYDDLGNSGHFTIIYNQGFEIVLNDYKWFAFFKYKEEGSKVTTYCNETMTGWVHDVLGRNWACFTGKKVGTASENVYVNIAHLKNSQEKYSNRLYKYDHNFVKAINAIQKSWTATTYMEYETLTLGDMIRRSGGHSRKIPRPKPAPLTAEIQQKILHLPTSWDWRNVHGINFVSPVRNQASCGSCYSFASMGMLEARIRILTNNSQTPILSPQEVVSCSQYAQGCEGGFPYLIAGKYAQDFGLVEEACFPYTGTDSPCKMKEDCFRYYSSEYHYVGGFYGGCNEALMKLELVHHGPMAVAFEVYDDFLHYKKGIYHHTGLRDPFNPFELTNHAVLLVGYGTDSASGMDYWIVKNSWGTGWGENGYFRIRRGTDECAIESIAVAATPIPKL
Open
Disease
Bronchiectasis
Approved Drug
0
Clinical Trial Drug
2 +
Discontinued Drug
0

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Detailed Information

The CTSC gene encodes a member of the cysteine peptidase family known as Cathepsin C, which plays an important role in immune system cells. As a lysosomal cysteine protease, the result of the CTSC gene participates in the triggering of many intracellular serine proteases, especially in neutrophils and other defense cells. This gene creates several versions of itself by a process called selective splicing, and at least one of these versions makes a precursor protein. These precursor proteins are turned into pairs made up of heavy and light chains linked together by disulfide bonds. This process is important for the folding and stability of the mature enzyme, with parts of the propeptide serving as intramolecular chaperones to help enzyme folding.

Cathepsin C needs salt to work and can break down glucagon. Mutations affecting this enzyme can lead to inherited diseases such as Papillon-Lefevre syndrome, marked by palmoplantar keratosis and periodontitis.

Activation Mechanism and Target Functions of Cathepsin C

Cathepsin C works inside cells and is also important for different natural system activities. Cathepsin C can trigger certain enzymes called serine proteases, including neutrophil elastase (NE), proteinase 3 (PR3), and cathepsin G (CatG), through its dipeptidyl peptidase action. These proteases are important for defensive reactions, especially when neutrophils are activated. Cathepsin C, with its unique catalytic process, helps in turning these serine proteases into their active forms to fight foreign invaders.

These serine proteases are commonly found in immune cells, especially in neutrophils, monocytes, mast cells, and lymphocytes. Their stimulation is important for how the immune system responds to diseases and inflammation. Cathepsin C helps break down proteins in these cells, but it also plays a part in cell communication and managing the defense system. For example, it can improve the ability of neutrophils and other immunity cells to fight off diseases by activating certain enzymes inside the cells.

Figure 1 illustrates the role of DPP1 in activating neutrophil serine protease (NSP) proenzymes during neutrophil differentiation, enabling neutrophils to migrate to infection sites and release NSPs, with their activity being regulated by inhibitors like alpha-1 antitrypsin.Figure 1. DPP1 activates NSP proenzymes during neutrophil differentiation. (Chalmers JD, et al., 2023)

DPP1 and Neutrophil-associated Diseases

DPP1's main function is to activate neutrophil serine proteases, including neutrophil elastase, proteinase 3, and CatG. Research indicates that the loss of DPP1 function in certain inflammatory diseases associated with neutrophils may exacerbate the condition. For example, in non-cystic fibrosis bronchiectasis (NCFBE), elevated NE activity in sputum is closely related to acute pulmonary exacerbations and reduced lung function. Additionally, the excessive activity of PR3 and CatG may significantly contribute to disease progression.

Studies show that DPP1 deficiency not only worsens the aforementioned inflammatory pathologies but also affects normal immune cell function, particularly neutrophil-related immune defense functions. Furthermore, DPP1's role in immune cells extends beyond protease activation to include regulatory mechanisms of the immune system, cytokine release, and cell migration abilities. Therefore, DPP1 is not only a critical biomarker but also a potential target for treating various immune-mediated diseases.

Immune Defense and Inflammation of Neutrophils

Neutrophils are important immune cells in the body's first line of defense. They help fight illnesses and remove harmful germs. One of their jobs is to use phagocytosis to remove harmful germs. Additionally, neutrophils can release neutrophil extracellular nets (NETs), net-like structures made of DNA, histones, and grainy proteins that physically catch and destroy pathogens.

Neutrophils are important for our immune system, but when they become too active, they can cause tissue damage and contribute to ongoing inflammatory conditions. Research has found that the action of neutrophil elastase (NE) is strongly linked to illnesses such as chronic obstructive lung disease (COPD) and bronchiectasis.

Genetic Defects and Disease Occurrence

Defects or inactivation of the CTSC gene can lead to various immune-related diseases. The most archetypal disease is Papillon-Lefevre syndrome (PLS), an autosomal recessive disorder caused by CTSC gene mutations. Patients with PLS typically exhibit palmoplantar keratosis, severe periodontitis, and premature loss of both primary and permanent teeth. Despite the preserved bacteria-clearing function mediated by neutrophils, these patients show significant defects in neutrophil chemotaxis, inflammatory cytokine release, and NET formation.

The impact of genetic defects on the immune system manifests not only as a loss of immune cell function but also as a disruption of neutrophil activation mechanisms. While neutrophils in PLS patients can achieve a degree of pathogen clearance, their activity is substantially lower than normal. This indicates that despite the loss of DPP1, the immune system can maintain some functionality, albeit with limitations. Consequently, DPP1 deficiency or impaired functionality provides vital clues for studying adaptive and compensatory mechanisms in the immune system.

Therapeutic Potential of DPP1 as a Target

Researchers are becoming more interested in tailored treatment that focuses on DPP1 because it plays an important part in different immune-related diseases. Changing how DPP1 works can lower inflammation caused by neutrophils, which helps decrease the chances of long-lasting inflammatory illnesses. For example, a lack of DPP1 might be strongly related to long-lasting inflammation, autoimmune diseases, and cancers. Blocking DPP1 activity or fixing its function with gene therapy might be a possible way to treat these diseases.

Even though addressing DPP1 has promise, there are still many hurdles to making it work in practice. More study is needed to carefully control DPP1 activity and prevent too much reduction of the defense system. Inhibiting DPP1 can help reduce inflammation caused by neutrophils, but to get the best results in real-life treatments, we need more clinical studies and studies.

References:

  1. Chalmers JD, Kettritz R, et al. Dipeptidyl peptidase 1 inhibition as a potential therapeutic approach in neutrophil-mediated inflammatory disease. Front Immunol. 2023 Dec 14;14:1239151.
  2. Patel KV, Sarraju A, et al. Cardiovascular Effects of Dipeptidyl Peptidase-4 Inhibitors and Glucagon-Like Peptide-1 Receptor Agonists: a Review for the General Cardiologist. Curr Cardiol Rep. 2020 Aug 8;22(10):105.
  3. Gallwitz B. GLP-1 agonists and dipeptidyl-peptidase IV inhibitors. Handb Exp Pharmacol. 2011;(203):53-74.
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