Cysteine proteases as disease markers

doi:10.1016/j.cccn.2003.12.016

Clinica Chimica Acta

Volume 342, Issues 1–2, April 2004, Pages 41-69

https://doi.org/10.1016/j.cccn.2003.12.016 Get rights and content

Abstract

This review comprises issues concerning cysteine cathepsins (CCs): human peptidases belonging to papain family (C1) of clan CA of cysteine proteases: cathepsins B, L, H, S, K, F, V, X, W, O and C. The involvement of these enzymes in physiological and pathological processes is described, especially with respect to their application as diagnostic and prognostic markers. They participate in precursor protein activation (including proenzymes and prohormones), MHC-II-mediated antigen presentation, bone remodeling, keratinocytes differentiation, hair follicle cycle, reproduction and apoptosis. Cysteine cathepsins upregulation has been demonstrated in many human tumors, including breast, lung, brain, gastrointestinal, head and neck cancer, and melanoma. Besides cancer diseases, they have been implied to participate in inflammatory diseases, such as inflammatory myopathies, rheumatoid arthritis, and periodontitis. Also, certain hereditary disorders are connected with mutations in CCs genes, what is observed in pycnodysostosis resulted from catK gene mutation and Papillon–Lefevre and Haim–Munk syndrome caused by catC gene defect. The potential application of cysteine cathepsins in diagnosis and/or prognosis is discussed in cancer diseases (breast, lung, head and neck, ovarian, gastrointestinal cancers, melanoma), as well as other disorders (periodontitis, rheumatoid arthritis, osteoarthritis).

Introduction

This review comprises issues concerning human peptidases belonging to papain family (C1) of clan CA of cysteine proteases: cathepsins B, L, H, S, K, F, V, X, W, O and C. The classification of cysteine proteases can be found in the MEROPS database [1], reviewed in Ref. [2]. Since these enzymes contain cysteine in their active site, and all of them are termed cathepsins, they can be called cysteine cathepsins (CCs) (to differentiate them from cathepsins belonging to serine or aspartate proteases, such as cathepsin G or cathepsin D, respectively). The classification of human cysteine cathepsins is shown in Table 1. The best known CCs, cathepsins B, L and H, are distributed ubiquitously in most tissues, where they catalyze protein hydrolysis within the lysosomes. Similar common expressions show cathepsins F, O, X and C, whereas cathepsins S, K, W and V are comprised to specific tissues (Table 2). Except for cathepsin C, all of the other CCs are monomers consisting of two domains, R (right) and L (left), which are formed in a V-shaped configuration. At the bottom of the V cleft, active site aminoacids; cysteine and histidine are situated [3]. Cysteine cathepsins are synthesized as 30–50 kDa preproenzymes, directed into lysosomes where they serve their function of protein hydrolysis. After signal peptides removal, the molecular mass of these enzymes remains within the range of around 20–35 kDa. Genes encoding CCs consist of about 10 exons separated by introns. Cathepsin C differs from the rest of these proteases both at the genetic and protein level. Its gene comprises only two exons and one intron. Also, the proteinaceous product of the gene expression is different in comparison with other enzymes; cathepsin C consists of four identical 50 kDa monomers and exhibits the ability of simultaneous joining four substrate molecules [4]. Another distinguished enzyme belonging to CCs is cathepsin W. Unlike other cathepsins, which in physiological conditions occur within lysosomes, it has been localized within the endoplasmic reticulum of natural killer cells [5].

Section snippets

Physiological role of cysteine cathepsins

Except for the well-known function of CCs within the lysosomes, consisting in protein degradation, various specific physiological roles have been ascribed to these enzymes. They are involved in precursor protein activation (including proenzymes and prohormones), MHC-II-mediated antigen presentation, bone remodeling, keratinocytes differentiation, hair follicle cycle, reproduction and apoptosis.

Cancer

The information concerning participation of cysteine cathepsins in cancer diseases has been presented in several recent review papers. The possible role of CCs (especially cathepsin B) in cancer development has been discussed by Koblinski et al. [63] and Yan et al. [64], and the usefulness of these enzymes in diagnosis and prognosis has been analyzed by Kos et al. [65] and Lah and Kos [66]. Therefore, in the present paper the general involvement of CCs in cancer progression will be summarized

Concluding remarks

In the light of the available at present information, it could be assumed that in some disorders CCs can be applied as diagnostic and prognostic markers. However, even in the case of the best-studied cathepsins B and L, experimental data coming from multiple sources are often ambiguous. The discrepancies result from separate approaches to an experimental design, which includes differences in methodology (various assays determining an enzyme at mRNA, protein or activity level), patients

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ReviewCysteine proteases as disease markers

Abstract

Introduction

Section snippets

Physiological role of cysteine cathepsins

Cancer

Concluding remarks

J. Biol. Chem.

J. Biol. Chem.

FEBS Lett.

FEBS Lett.

J. Neuroimmunol.

Immunity

Immunity

Immunity

Clin. Chim. Acta

Am. J. Pathol.

Am. J. Pathol.

Dev. Biol.

Arch. Biochem. Biophys.

Am. J. Pathol.

J. Biol. Chem.

Gastroenterology

Clin. Chim. Acta

Eur. J. Cancer

Exp. Cell Res.

Cancer Lett.

Eur. J. Cancer

Evolutionary lines of cysteine peptidases

Biol. Chem.

Structural and functional aspects of papain-like cysteine proteinases and their protein inhibitors

Biol. Chem.

Human cathepsin W, a cysteine protease predominantly expressed in NK cells, is mainly localized in the endoplasmic reticulum

J. Immunol.

Evidence for extracellularly acting cathepsins mediating thyroid hormone liberation in thyroid epithelial cells

Endocrinology

Thyroid functions of mouse cathepsins B, K, and L

J. Clin. Invest.

Role of cathepsin B in intracellular trypsinogen activation and the onset of acute pancreatitis

J. Clin. Invest.

Dipeptidyl peptidase I is required for the processing and activation of granzymes A and B in vivo

Proc. Natl. Acad. Sci. U. S. A.

Dipeptidyl peptidase I activates neutrophil-derived serine proteases and regulates the development of acute experimental arthritis

J. Clin. Invest.

Involvement of cathepsin H in the processing of the hydrophobic surfactant-associated protein C in type II pneumocytes

Am. J. Respir. Cell Mol. Biol.

Cysteine peptidases of mammals: their biological roles and potential effects in the oral cavity and other tissues in health and disease

Crit. Rev. Oral. Biol. Med.

Individual cathepsins degrade immune complexes internalized by antigen-presenting cells via Fcgamma receptors

Eur. J. Immunol.

Cathepsin L regulates CD4+ T cell selection independently of its effect on invariant chain: a role in the generation of positively selecting peptide ligands

J. Exp. Med.

Cathepsins B and D are dispensable for major histocompatibility complex class II-mediated antigen presentation

Proc. Natl. Acad. Sci. U. S. A.

Emerging roles for cysteine proteases in human biology

Annu. Rev. Physiol.

Importance of lysosomal cysteine proteases in lung disease

Respir. Res.

Cathepsin S activity regulates antigen presentation and immunity

J. Clin. Invest.

Cathepsin S controls the trafficking and maturation of MHC class II molecules in dendritic cells

J. Cell Biol.

Specific role for cathepsin S in the generation of antigenic peptides in vivo

Eur. J. Immunol.

Proteases involved in MHC class II antigen presentation

Immunol. Rev.

Fc epsilon receptor I on dendritic cells delivers IgE-bound multivalent antigens into a cathepsin S-dependent pathway of MHC class II presentation

J. Immunol.

Differential regulation of cathepsin S and cathepsin L in interferon γ-treated macrophages

J. Exp. Med.

Modulation of the endosomal and lysosomal distribution of cathepsins B, L and S in human monocytes/macrophages

Biol. Chem.

Cathepsin S activity is detectable in human keratinocytes and is selectively upregulated upon stimulation with interferon-gamma

J. Invest. Dermatol.

Role for cathepsin F in invariant chain processing and major histocompatibility complex class II peptide loading by macrophages

J. Exp. Med.

Cathepsin L: critical role in Ii degradation and CD4 T cell selection in the thymus

Science

Nackt (nkt), a new hair loss mutation of the mouse with associated CD4 deficiency

Immunogenetics

Review
Cysteine proteases as disease markers

Cathepsin L regulates CD4⁺ T cell selection independently of its effect on invariant chain: a role in the generation of positively selecting peptide ligands