Cathepsin V: Molecular characteristics and significance in health and disease

https://doi.org/10.1016/j.mam.2022.101086Get rights and content

Highlights

  • Human cathepsin V (cathepsin L2) is closely related to cathepsin L.

  • Cathepsin V displays a unique and potent elastolytic activity among mammalian proteases.

  • Cathepsin V participates in diverse biological processes (e.g., MHC class II antigen presentation).

  • Increased expression of cathepsin V is correlated with malignancies and vascular diseases.

Abstract

Human cysteine cathepsins form a family of eleven proteases (B, C, F, H, K, L, O, S, V, W, X/Z) that play important roles in a considerable number of biological and pathophysiological processes. Among them, cathepsin V, also known as cathepsin L2, is a lysosomal enzyme, which is mainly expressed in cornea, thymus, heart, brain, and skin. Cathepsin V is a multifunctional endopeptidase that is involved in both the release of antigenic peptides and the maturation of MHC class II molecules and participates in the turnover of elastin fibrils as well in the cleavage of intra- and extra-cellular substrates. Moreover, there is increasing evidence that cathepsin V may contribute to the progression of diverse diseases, due to the dysregulation of its expression and/or its activity. For instance, increased expression of cathepsin V is closely correlated with malignancies (breast cancer, squamous cell carcinoma, or colorectal cancer) as well vascular disorders (atherosclerosis, aortic aneurysm, hypertension) being the most prominent examples. This review aims to shed light on current knowledge on molecular aspects of cathepsin V (genomic organization, protein structure, substrate specificity), its regulation by protein and non-protein inhibitors as well to summarize its expression (tissue and cellular distribution). Then the core biological and pathophysiological roles of cathepsin V will be depicted, raising the question of its interest as a valuable target that can open up pioneering therapeutic avenues.

Introduction

Cathepsin V (cathepsin L2, EC 3.4.22.43) is a lysosomal cysteine protease related to papain from Carica papaya (C1 family, clan CA; MEROPS protease classification system, Rawlings et al., 2018) and is part of the eleven cysteine cathepsins (B, C, F, H, K, L, O, S, V, W, X/Z) present in humans. This protease has been discovered (as cathepsins K, S, X/Z, F, O, and W) in the 1990s, later than cathepsin C which was identified in the 1940s, and cathepsins B, H and L which were characterized during the second half of the previous century (Greenbaum and Fruton, 1957; Kirschke et al., 1979). Nevertheless, cathepsin V is currently gaining a growing interest according to its diverse roles in physiological and pathological processes, including MHC class II-restricted antigen presentation, corneal neovascularization, vascular diseases, or cancers. In this review, we summarize molecular characteristics and functional properties of cathepsin V in health and disease covering over twenty years of research.

Section snippets

Nomenclature, genomic organization, and gene expression

Human cathepsin V (also originally designated as cathepsin U) was first cloned from cDNA libraries derived from the corneal epithelium, thymus, and testis, by three independent research groups (Adachi et al., 1998; Santamaría et al., 1998; Brömme et al., 1999). Cathepsin V gene (CTSL2/CTSV) was localized by FISH analysis on the long arm of human chromosome 9q22.2, a site adjacent to the cathepsin L locus (CTSL1) (Itoh et al., 1999). Except for cathepsin B gene that is present on the short arm

Cornea

Keratoconus corneas (KC) is an eye disorder (blurred vision, increased sensitivity to bright light and glare) resulting in a progressive thinning of the cornea likely due to collagen deficiency in cornea, associated with oxidative stress. It was proposed that the proteolytic degradation of some BM constituents (i.e., fibronectin, laminins, collagens, and proteoglycans) may be related, in concert with other thiol-dependent cathepsins, to an increase of cathepsin V mRNA expression and its

Concluding remarks

This review aims to summarize current knowledge on cysteine cathepsin V, covering from its discovery in the late nineties to latest advances exploring cathepsin V expression (tissue and cellular distribution), enzymatic activity, and regulation by protein inhibitors and non-proteinogenic effectors. Although cathepsin V is still less characterized and investigated than some counterparts, i.e., cathepsins B, C, K, L, and S, there are increasing clues that cathepsin V plays a pivotal role in a

Author contributions

F.L. drafted the review article; F.L. and G.L. wrote the article; F.L. coordinated the writing of the review; T.C. and F.L. prepared the tables and the figures; T.C., G.L., and F.L. participated in bibliographic research; T.C. and A.S. edited the article. All authors have read and agreed to the published version of the manuscript.

Declaration of competing interest

The authors declare no conflict of interest. The funding sources had no role in the writing of the manuscript.

Acknowledgments

We acknowledge the University of Tours and the Institut National de la Santé et de la Recherche Médicale (INSERM) for institutional funding, and la Région Centre-Val de Loire, France (Pirana project; number 2019–00134916). Dr Thibault Chazeirat is a former recipient of a doctoral grant from the Ministère de l’Enseignement Supérieur, de la Recherche, et de l’Innovation (MESRI), France.

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