Cathepsin B is a papain-family cysteine protease that is normally located in lysosomes , where it is involved in the turnover of proteins and plays various roles in maintaining the normal metabolism of cells. This protease has been implicated in pathological conditions , e.g. , tumor progression and arthritis. In disease conditions , increases in the expression of cathepsin B occur at both the gene and protein levels. Cathepsin B is synthesized as a preproenzyme and the primary pathways for its normal trafficking to the lysosome utilize mannose 6-phosphate receptors (MPRs). Mature cathepsin B has the ability to degrade several extracellular matrix components at both neutral and acidic pH and has been implicated in the progression of several Human and rodent tumors progression and arthritis. Cathepsin B expression is increased in many Human cancers at the mRNA , protein and activity levels. It is also frequently overexpressed in premalignant lesions , an observation that associates this protease with local invasive stages of cancer. Increased expression of cathepsin B in primary cancers , and especially in preneoplastic lesions , suggests that this enzyme might have pro-apoptotic features. Active cathepsin B is also secreted from tumours , a mechanism likely to be facilitated by lysosomal exocytosis or extracellular processing by surface activators. Cathepsin B is localized to caveolae on the tumour surface , where binding to the annexin II heterotetramer occurs. Thus CTSB is suggested as a tumor marker. Additionally , Cathepsin B can degrade extracellular matrix proteins , such as collagen IV and laminin , and can activate the precursor form of urokinase plasminogen activator (uPA) , perhaps thereby initiating an extracellular proteolytic cascade.
CTSD localizes to the lysosome and consists of a light chain and a heavy chain. CTSD is expressed in epithelial cells as well as in macrophages.CTSD is a lysosomal aspartyl protease that depends critically on protonation of its active site Asp residue and gets activated at pH 5 in endosome of hepatocytes. It has been suggested to facilitate cancer cell migration and invasion by digesting the basement membrane, extracellular matrix and xonnective tissue. In addition, CTSD has been used as a breast cancer tumor marker.
Cathepsin E Protein (CTSE Protein) is a member of the peptidase C1 family that is a gastric aspartic protease that functions as a disulfide-linked homodimer. Cathepsin E Protein (CTSE Protein) is predominantly present in the cells of immune system and is frequently implicated in antigen processing via the MHC classⅡ pathway which however does not appear to be involved in the digestion of dietary protein. The protein has a specificity similar to that of pepsin and pepsin. Cathepsin E Protein (CTSE Protein) is found in highest concentration in the surface of epithelial mucus-producing cells of the stomach and also been found in more than half of the gastric cancers. It appears, therefore, to be an oncofetal antigen.
Cathepsin E is encoded by the ctse gene, exists in the homodimer forms, belongs to the peptidase A1 family. Cathepsin E high expressed in the stomach, clara cells and alveolar macrophages of lung, brain microglia, spleen and activated B-lymphocytes. Cathepsin E may involve in the processing of antigenic peptides during MHC class II-mediated antigen presentation, play a role in activation-induced lymphocyte depletion in the thymus, and in neuronal degeneration and glial cell activation in the brain.
Proinflammatory cytokines decreased the expression of CTSH in human islets and primary rat beta-cells, and overexpression of CTSH protected insulin-secreting cells against cytokine-induced apoptosis.
Cathepsin L is a lysosomal cysteine protease that plays a major role in intracellular protein catabolism, and is potent in degrading collagen, laminin, elastin, as well as alpha-1 protease inhibitor and other structural proteins of basement membranes. Like many proteases, Cathepsin L is synthesized as an inactive preproenzyme, and cleavage of the 96-residue proregion is necessary to generate the fully active 221-residue mature enzyme. Studies have demonstrated that cleavage of the proregion occur autocatalytically under acidic conditions. The enzyme takes part in nutrient acquisition by catabolizing host proteins to absorbable peptides, facilitates the migration of the parasite through the host intestine and liver by cleaving interstitial matrix proteins such as fibronectin, laminin and native collagen and is implicated in the inactivation of host immune defenses by cleaving immunoglobulins. Recently, Cathepsin L has been shown to suppress Th1 immune response in infected laboratory animals making them susceptible to concurrent bacterial infections. Cathepsin L is synthesized in large amounts and secreted by many malignantly transformed cells, and induced by growth factors and tumor promoters. In addition to its role in protein degradation, evidence has accumulated for the participation of Cathepsin L in various physiological and pathological processes, such as tumor invasion and metastasis, bone resorption, spermatogenesis, and arthritis. Accordingly, Cathepsin L may prove useful as a diagnostic or prognostic marker of human tumor malignancy.
Cathepsin S (CTSS), one of the lysosomal proteinases, has many important physiological functions in the nervous system, especially in process of extracellular matrix degradation and endocellular antigen presentation. CTSS is synthesized as inactive precursor of 331 amino acids consisting of a 15-aa signal peptide, a propeptide of 99 aa, and a mature polypeptide of 217 aa. It is activated in the lysosomes by a proteolytic cleavage of the propeptide. Cathepsin S is expressed in the lysosome of antigen presenting cells, primarily dendritic cells, B-cells and macrophages. Compared with other lysosomal cysteine proteases, cathepsin S has displayed some unique characteristics. Cathepsin S is most well known for its critical function in the proteolytic digestion of the invariant chain chaperone molecules, thus controlling antigen presentation to CD4+ T-cells by major histocompatibility complex (MHC) class II molecules or to NK1.1+ T-cells via CD1 molecules. Cathepsin S also appears to participate in direct processing of exogenous antigens for presentation by MHC class II to CD4+ T-cells, or in cross-presentation by MHC class I molecules to CD8+ T-cells. In addition, although direct evidence is still lacking, in its secreted form cathepsin S is implicated in degradation of the extracellular matrix, which may contribute to the pathology of a number of diseases, including arthritis, atherosclerosis, neurological diseases and chronic obstructive pulmonary disease.
Cathepsin S is a lysosomal enzyme that belongs to the papain family of cysteine proteases. This protein is expressed by antigen presenting cells including macrophages, B-lymphocytes, dendritic cells and microglia. Moreover, cathepsin S is expressed in some epithelial cells. Compared with the abundant cathepsins B, L and H, cathepsin S shows a restricted tissue distribution, with highest levels in spleen, heart, and lung. In addition, evidences indicated that cathepsin S generates A beta from amyloidogenic fragments of beta APP in the endosomal/lysosomal compartment, and is implicated in the pathogenesis of Alzheimer’s disease (AD) and Down Syndrome (DS).
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