The gene for human cathepsin H is located on chromosome 15q24-q25 and contains 12 exons spanning over 23 kb of genomic sequences. The junctions between the exons and 11 introns conform to the GT-AG rule. The preproenzyme transcript length is 1005 bp.

The cathepsin H gene has a TATA- and CAAT-less promoter and upstretream of exon 1 only one GC box was detected, suggesting the presence of one more exon. Two different forms of cathepsin H cDNA, the full-length form (CTSH) and a truncated form with deletion of 12 amino acids at the signal peptide region (CTSHdelta10-21), were identified in prostate tissues and cancer cell lines.

Cathepsin H belongs to the superfamily of papain-like cysteine proteases. It is synthesized as a preproenzyme of 335 amino acid residues with a calculated Mr of 37 403. It is proteolytically processed to an active single chain, i.e. mature form within the endosomes/lysosomes. A unique feature of this enzyme is that it acts as both an aminopeptidase and an endopeptidase although the latter activity is much lower than the former activity. Sequencing data revealed that in addition to the heavy and light chains, which are typically found in a number of mammalian papain-like cysteine proteases, cathepsin H contains also an octapeptide EPQNCSAT originating from the propeptide, termed the mini-chain. It was shown that the mini-chain is disulfide linked to Cys205 of the main body of the enzyme and involved in the aminopeptidase activity of the enzyme. It was concluded that the mini-chain plays a key role in substrate recognition, and that the carbohydrate residues attached to the body of the enzyme are involved in the positioning the mini-chain in the active-site cleft. Procathepsin H has three potential carbohydrate binding sites. Glycosilation has been confirmed on Asn230 and on the mini-chain Asn101 of the mature enzyme. The recombinant form of human cathepsin H lacking the mini-chain was shown to be an endopeptidase. Cathepsin H hidrolyzes endopeptidase substrates such as Bz-Arg+NHNap, Bz-Arg+NHMec, Bz-Phe-Val-Arg+NHMec, and acts on Pro-Gly+Phe and Pro-Arg+NHNap much like a dipeptidyl-peptidase. It was shown to cleave several proteins preferring hydrophobic residues at P2 and P3, however the endopeptidase activity of the enzyme is limited. Collagen and laminin, for instance, were not degraded by cathepsin H. Naturally occurring inhibitors of cathepsin H are the cystatins, a2-macroglobulin and antigens from mouse cytotoxic lymphocytes CTLA-2ß.

Cathepsin H expression is ubiquitous, with very high expression in the kidney. There is growing evidence that the expression of cathepsin H is increased in diseases including breast, colorectal and prostate carcinoma, melanoma and gliomas. In contrast, decreased cathepsin H expression has been reported in squamous cell carcinoma of the head and neck. Other studies have found a higher cathepsin H expression in well-differentiated pancreatic cancer cells compared with less well-differentiated cancer cells.

Cathepsin H is located manly at the endosomal-lysosomal compartments. Only 10 % of the enzyme is secreted. It has been shown that substantial concentrations of cathepsin H circulate in the blood.

Cathepsin H is one of the lysosomal cysteine proteinases, which are involved in intracellular protein degradation. It is one of the few noncomplement proteases that cleave native C5 to generate the potent chemotaxin C5a. Cathepsin H was detected in extracellular compartments of atherosclerotic plaques. Although the pathogenic potential of cathepsin H in the development of the late, unstable plaque is quite evident, there is the possibility that this protease may play a role in early atherogenesis. Furthermore, it was found that cathepsin H could contribute to the transformation of LDL in monocyte-derived foam cells. Recently the enzyme was shown to be essential in one of the processing steps of hydrophobic surfactant-associated protein C.
Cathepsin H is overexpressed in different tumour cells. However, the role of cathepsin H in tumour progression is not well understood. A possible function of cathepsin H in tumour progression is its ability to degrade fibrinogen and fibronectin, suggesting that, along with other proteases, cathepsin H may be involved in the destruction of extracellular matrix components leading to cancer proliferation, migration, and metastasis.

Cathepsins H exhibit a high degree of sequence homology to cathepsin B and other cysteine proteinases of the C1 (papain) family.

Not yet reported

Not yet reported