Cathepsin S: therapeutic, diagnostic, and prognostic potential

Abstract

Cathepsin S is a member of the cysteine cathepsin protease family. It is a lysosomal protease which can promote degradation of damaged or unwanted proteins in the endo-lysosomal pathway. Additionally, it has more specific roles such as MHC class II antigen presentation, where it is important in the degradation of the invariant chain. Unsurprisingly, mis-regulation has implicated cathepsin S in a variety of pathological processes including arthritis, cancer, and cardiovascular disease, where it becomes secreted and can act on extracellular substrates. In comparison to many other cysteine cathepsin family members, cathepsin S has uniquely restricted tissue expression and is more stable at a neutral pH, which supports its involvement and importance in localised disease microenvironments. In this review, we examine the known involvement of cathepsin S in disease, particularly with respect to recent work indicating its role in mediating pain, diabetes, and cystic fibrosis. We provide an overview of current literature with regards cathepsin S as a therapeutic target, as well as its role and potential as a predictive diagnostic and/or prognostic marker in these diseases.

Neutrophilic Cathepsin C Is Maturated by a Multistep Proteolytic Process and Secreted by Activated Cells during Inflammatory Lung Diseases

“…Hence active NSPs together with CatC can be secreted to fulfill additional extracellular functions in peripheral tissues. Our view is consistent with previous observations on neutrophils (20,39) and monoblastic U937 cells (1) and with ongoing clinical trials that evaluate the potential of CatS inhibitors in patients with psoriasis or rheumatoid arthritis (40).…”

Inhibitors and Antibody Fragments as Potential Anti-Inflammatory Therapeutics Targeting Neutrophil Proteinase 3 in Human Disease

“…Pro-CatC maturation is mainly controlled by cysteine proteases, with cathepsin S (CatS) being a major actor in human neutrophil precursors cells (Hamon et al, 2016). Several CatS inhibitors were recently developed and are currently in clinical trials (Wilkinson et al, 2015). The combination of CatS and CatC inhibitors should not only reduce the NSP burden within neutrophils, but it should also impair cell recruitment at inflammatory sites.…”

Cathepsin S–Dependent Protease–Activated Receptor-2 Activation: A New Mechanism of Endothelial Dysfunction

“…One member of this family, cathepsin S, has been implicated in the pathogenesis of a range of disease states. 6 Cathepsin S contributes to protein degradation in the endosomal/lysosomal pathway, including proteolytic degradation of the li chaperone protein, which allows peptide antigens to bind to MHC class 2 molecules and be presented to T lymphocytes. In addition to its well defined role in the adaptive immune response, cathepsin S can also be secreted.…”

“…Cathepsin S enzymatic activity operates across a relatively wide range of pH values, which enables activity in acidic endosomes as well as the more neutral conditions of the extracellular space, in which it can cleave substrates, such as elastin, E-cadherin, secretory leukoprotease inhibitor, junctional adhesion molecule-B, and PAR-2. 6 One distinct feature of cathepsin S is that its expression is largely restricted to leukocyte subsets, particularly macrophages, although cathepsin S expression can be induced in a variety of nonleukocyte cell types. Experimental studies using cathepsin S gene-deficient mice or cathepsin S inhibitors have defined a role for this enzyme in autoimmune diseases, atherosclerosis, airway hyper-responsiveness, cancer metastasis, neovascularization, and neuropathic pain.…”

“…Experimental studies using cathepsin S gene-deficient mice or cathepsin S inhibitors have defined a role for this enzyme in autoimmune diseases, atherosclerosis, airway hyper-responsiveness, cancer metastasis, neovascularization, and neuropathic pain. 6 In addition, elevated serum levels of cathepsin S have been described in a number of diseases and correlate with insulin resistance, diabetes, atherosclerosis, and heart disease. 7,8 The study by Kumar et al 5 proposes that macrophagederived cathepsin S induces endothelial cell damage by activation of PAR-2 on the endothelial cell surface.…”