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Page 6 of 17 Stojkovska Docevska et al. Rare Dis Orphan Drugs J 2023;2:14 https://dx.doi.org/10.20517/rdodj.2023.09

these cells and their effector peptidases. These pathologies include various inflammatory and autoimmune
[74]
[36]
[73]
[40]
diseases such as arthritis [71,72] , asthma , abdominal aortic aneurysm , cystic fibrosis , pancreatitis ,
[76]
[36]
neuroinflammation [70,75] inflammatory lung diseases including bronchiectasis , and indirectly chronic
[77]
obstructive pulmonary disease . Inhibition of cathepsin C activity in bone marrow was shown to be an
effective method of silencing neutrophil serine peptidases, underscoring the importance of cathepsin C as a
target for the treatment of these diseases , as discussed in more detail in the next section.
[78]
As expected for a ubiquitously expressed protein, physiological and pathological roles and substrates outside
of the immune system have also been described for cathepsin C. The best known pathological examples are
mutations in the CATC gene that cause the recessive hereditary diseases called Papillon-Lefèvre syndrome
(PLS) and Haim-Munk syndrome (HMS) [8-10] . Symptoms of both diseases include early periodontitis,
pathological thickening of the skin on the palms and feet, and increased susceptibility to infection, again
highlighting the important role of cathepsin C in the immune system . Neutrophil function is impaired
[11]
[79]
but not completely abolished . At the molecular level, mutations can result in truncated cathepsin C or
[9]
point mutations that cause loss of function . At the cellular level, autophagy is impaired, and treatment of
[8,9]
PLS patients with recombinant cathepsin C has been proposed as an approach to restore autophagic
function .
[80]
Several studies pointed to the roles of cathepsin C in the systemic regulation of metabolism. The earliest
study showed that cathepsin C inactivates the peptide hormone glucagon by sequential removal of
[21]
dipeptides from the N-terminus . Cathepsin C, in conjunction with plasma glutamate carboxypeptidase,
was also shown to be involved in the extracellular processing of thyroglobulin, which is coupled with the
release of the stress hormone thyroxin from the thyroid gland . Furthermore, it has been shown to
[81]
participate in lysosomal degradation of the digestive peptide hormone cholecystokinin together with
tripeptidyl peptidase I (TPP-1) . Due to their overlapping N-terminal exopeptidase activity, it was first
[82]
suggested that cathepsin C may compensate for lack of TPP-1 activity and be used to alleviate the
deleterious effects of TPP-1 loss-of-function mutations, which cause the lethal neurodegenerative lysosomal
storage disorder classical late-infantile neuronal ceroid lipofuscinosis (CLN2) [82,83] . Unfortunately, studies
using mouse models of the disease have invalidated this approach, as cathepsin C did not functionally
[84]
compensate for the loss of TPP-I activity in the brain .

There is also increasing evidence that cathepsin C contributes to the progression of various cancers such as
squamous cell carcinoma , hepatocellular carcinoma , gastric cancer , colorectal cancer , breast
[85]
[87]
[54]
[86]
cancer , and so on. In these cancers, pathological cathepsin C activity originates either from tumor stromal
[88]
cells or directly from tumor cells [85-88] , and contributes to tumorigenesis via diverse cellular and molecular
[54]
mechanisms. In squamous cell carcinoma, increased activity of cathepsin C was observed in fibroblasts and
bone marrow-derived cells of the tumor stroma, which promoted carcinogenesis . In hepatocellular
[54]
carcinoma, cathepsin C/TNFα/p38 MAPK interplay was observed similar to that contributing to
macrophage M1 polarization , whereas in gastric and colorectal cancer, cathepsin C was associated with
[85]
dysregulation of autophagy [86,87] . In breast cancer, cathepsin C was found to be secreted from tumor cells and
to promote neutrophil recruitment during lung metastasis . A detailed expert review on the indirect and
[88]
direct roles of cathepsin C in cancer has been published recently .
[89]
In vitro, cathepsin C also plays a critical role in the permeabilization of the lysosomal membrane triggered
by the lysosomotropic detergent L-leucyl-leucine methyl ester (LLOMe), resulting in the release of
lysosomal hydrolases into the cytosol that ultimately triggers caspase-dependent apoptotic cell death.
Cathepsin C has been proposed to mediate lysosomal membrane permeabilization by catalyzing the