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Stojkovska Docevska et al. Rare Dis Orphan Drugs J 2023;2:14 https://dx.doi.org/10.20517/rdodj.2023.09 Page 5 of 17

[43]
protease 4 , as well as granzymes in cytotoxic T lymphocytes, and chymases in mast cells. All belong to the
chymotrypsin-like family, classified as clan PA, family S1, subfamily S1A in the MEROPS database of
[2]
peptidases . All are synthesized as preproenzymes and processed to inactive zymogens upon completion of
synthesis and ER import. The zymogens contain an N-terminal propeptide of two amino acid residues and
are converted to their active forms via a single cleavage by cathepsin C which removes the propeptide [44-46] .
This causes a conformational change that results in the formation of a catalytically competent active site.
The underlying molecular mechanism is well conserved in chymotrypsin-like peptidases and was also
[47]
[48]
studied at the molecular level for the activation of prochymase .
NSPs are synthesized at the promyelocyte stage. Proper timing of the N-terminal processing is essential for
their activity and optimal storage in azurophil granules. Activation normally occurs after the sorting of
zymogens to pregranule/granule compartments . Garwicz et al. have shown that while the N-terminal
[49]
propeptide is not strictly necessary for the sorting of neutrophil cathepsin G into the granules, premature
activation of the zymogen is deleterious . Similarly, abnormal processing in the absence of DPPI has been
[50]
shown for granzyme A, resulting in products cleaved at alternative locations by unknown peptidases .
[46]
NSPs can be either stored in an active form in the granules or secreted from the cell as zymogens in varying
proportions, depending on the individual peptidase . Activated neutrophils secrete stored, active NSPs as
[51]
[52]
soluble molecules or bound to chromatin in the form of neutrophil extracellular traps . Once released into
the extracellular environment, these pro-inflammatory peptidases can degrade various extracellular matrix
components, resulting in tissue damage and chronic inflammation .
[53]

Some tissue studies have provided evidence that mast cells are the predominant cathepsin C-expressing cells
in the non-inflamed airways of dogs and mouse skin . Studies in cultured cells suggested that some
[40]
[54]
[55]
cathepsin C is packaged and secreted in serine protein-rich mature granules . Whether cathepsin C, which
is released into the extracellular environment rich in cystatins and other potential inhibitors, can also act
outside the cell by cleaving extracellular proteins remains unclear, although some studies suggest it is
capable of doing so [40,41] . The repertoire of mast-cell peptidases activated by cathepsin C includes cathepsin G
and chymase [56-58] . Mast cells from cathepsin C-deficient mice express normal amounts of chymase, but it
[45]
has the form of an unprocessed proenzyme . The involvement of cathepsin C in the activation of tryptases
is less clear [45,59,60] . Recent studies suggest that cathepsin C is sufficient, but not necessary, for the complete
maturation of β-tryptases in human mast cells, and that one or more other cysteine cathepsins may take
over this role . Experiments in animal models support a role for cathepsin C in tryptase activation, as
[60]
[45]
tryptase activity is reduced but not absent in cathepsin C-deficient mice . In addition, studies in animal
models indicate that cathepsin C in mast cells increases the likelihood of fatal sepsis, suggesting a role for
cathepsin C in regulating interleukin-6 levels by regulating the production of tryptase and other interleukin-
6-degrading peptidases . Similarly, granzymes in cytotoxic T lymphocytes contain N-terminal pro-
[61]
dipeptides (usually Gly-Glu or Glu-Glu) [62,63] . In these cells, cathepsin C is present in secretory granules ,
[64]
and several studies have shown that cathepsin C can activate these peptidases in vitro [65-67] .

Roles in immunity other than activation of serine peptidases have also been described for cathepsin C.
Evidence points towards its regulatory role in macrophage polarization into the M1 phenotype via an
interplay with tumor necrosis factor α (TNFα), focal adhesion kinase (FAK) and the p38/mitogen-activated
protein kinase (MAPK) pathway [68,69] . Similarly, cathepsin C was shown to promote microglia M1
polarization in the brain .
[70]

The crucial role of cathepsin C in the activation of peptidases in immune cells suggests that its activity is
also an important factor in the development of pathological conditions associated with excessive activity of