CTSH

CTSH Background

Cathepsin H (CTSH) is a cysteine endopeptidase involved in protein degradation. CTSH is ubiquitously expressed in cells and tissues ^[1]. CTSH is mainly located at the endosomal-lysosomal compartments. Only 10 % of the enzyme is secreted. It has been shown that substantial concentrations of CTSH circulate in the blood. For preventing premature activation, CTSH is synthesized as a pre-pro-enzyme containing a prodomain and a mature (catalytic) domain ^[2]. Pre-pro-cathepsin H is proteolytically activated through a multistep process initially generating an intermediate pro-cathepsin H, which finally forms a single chain mature enzyme after the removal of the prodomain upon the low pH stimulation ^[3]. Yue Hao et al. demonstrated that pro-cathepsin H fails to autoactivate and requires other proteases such as cathepsin L for its activation ^[4]. Upon activation, CTSH predominantly exhibits as an aminopeptidase that cleaves a single N-terminal residue from a polypeptide chain ^[5]. The binding of the mini-chain (the octapeptide EPQNCSAT from the prodomain) to cathepsin H through a disulfide bond makes CTSH unique among papain-like cysteine proteases. And this is essential for the aminopeptidase activity ^[6]. It 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 positioning the mini-chain in the active-site cleft. Removal of the mini-chain makes the strong aminopeptidase activity of CTSH switch to the endopeptidase activity ^[7][8]. Many studies showed that CTSH participates in the lysosome rupture-induced apoptosis. CTSH was shown to be overexpressed in several pathological states, including carcinoma and melanoma ^[9][10]. Ablation of CTSH remarkably impaired angiogenic switching of the pre-malignant hyperplastic islets and reduced the number of subsequent tumors. Moreover, the tumor burden in CTSH-null RT2 mice was significantly reduced, in association with defects in the blood vasculature and increased apoptosis ^[11].

[1] Barrett A. J., Kirschke H. Cathepsin B, cathepsin H, and cathepsin L. Methods Enzymol 1981, 80, (Pt C) 535-561.
[2] Wiederanders, B., Kaulmann, G., and Schilling, K. (2003). Functions of propeptide parts in cysteine proteases. Curr. Protein Pept. Sci. 4, 309-26.
[3] Nishimura Y, Kato K Intracellular transport and processing of lysosomal cathepsin H [J]. Biochemical and biophysical research communications. 1987 ; 148 (1) : 329-334.
[4] Yue Hao, Whitney Purtha, et al. Crystal structures of human procathepsin H [J]. PLoS ONE 2018, 13(7): e0200374.
[5] Takahashi T, Dehdarani AH, et al. Porcine spleen cathepsin H hydrolyzes oligopeptides solely by aminopeptidase activity. The Journal of biological chemistry. 1988;263(22):10952.
[6] Baudys M, Meloun B, et al. S-S bridges of cathepsin B and H from bovine spleen: a basis for cathepsin B model building and possible functional implications for discrimination between exo- and endopeptidase activities among cathepsins B, H, and L. Biomed Biochim Acta. 1991;50:569-7.
[7] Vasiljeva O, Dolinar M, et al. Recombinant human cathepsin H lacking the mini-chain is an endopeptidase. Biochemistry. 2003, Nov 25; 42(46):13522-8.
[8] Dodt J, Reichwein J. Human cathepsin H: deletion of the mini-chain switches substrate specificity from aminopeptidase to endopeptidase. Biol Chem. 2003;384(9):1327-2.
[9] Kos J, Stabuc B, et al. Cathepsins B, H, and L and their inhibitors stefin A and cystatin C in sera of melanoma patients. Clinical cancer research: an official journal of the American Association for Cancer Research. 1997;3(10):1815-2.
[10] del Re EC, Shuja S, et al. Alterations in cathepsin H activity and protein patterns in human colorectal carcinomas. Br J Cancer. 2000;82(7):1317-6.
[11] Gocheva V, Chen X, et al. Deletion of cathepsin H perturbs angiogenic switching, vascularization and growth of tumors in a mouse model of pancreatic islet cell cancer. Biol Chem. 2010 Aug; 391(8):937-45.