Cathepsin S is aprotein that in humans is encoded by theCTSSgene.[5] Transcript variants utilizing alternative polyadenylation signals exist for this gene.[5]
Cathepsin S is a lysosomal enzyme that belongs to thepapain-like protease family ofcysteine proteases. While its role in antigen presentation has long been recognized, recent research has highlighted its involvement in itch and pain, or nociception.[6][7] The nociceptive activity of cathepsin S results from its role as a signaling molecule through the activation of protease-activated receptors 2 and 4, which are members of the G-protein-coupled receptor family.[8]
Cathepsin S influences blood vessel permeability andangiogenesis due to its elastolytic and collagenolytic activities. For example, cleavage of laminin-5 by cathepsin S generates proangiogenic peptides.[9]
Cathepsin S has a crucial role inantigen presentation. Major histocompatibility complex (MHC) class II molecules interact with peptide fragments for presentation on antigen-presenting cells. Cathepsin S degrades the invariant chain (Ii), which prevents antigen loading into the MHC complex. This degradation occurs in lysosomes after two initial cleavages byaspartyl proteases. Cathepsin S cleaves the remaining Ii fragment (IiP1), leaving a small portion (CLIP) directly associated with MHC II.
Proper degradation of Ii facilitates CLIP dissociation and antigen loading. Overexpression of cathepsin S may lead to premature Ii degradation, occasional antigen loading, and potential autoimmune responses. Conversely, inhibition of cathepsin S delays antigen loading, weakens immune responses, and results in uncleaved Ii fragments remaining on the MHC II surface, impairing T-cell proliferation. In macrophages, cathepsin S can be replaced bycathepsin F.
Cathepsin S is expressed by antigen-presenting cells such asmacrophages,B-lymphocytes,dendritic cells, andmicroglia. It is also produced by someepithelial cells, and its expression significantly increases in human keratinocytes upon stimulation with interferon-gamma. Inpsoriatickeratinocytes, its expression is elevated due to proinflammatory factors. However, cortical thymic epithelial cells do not express cathepsin S.
Unlike many members of the cysteine cathepsin family, cathepsin S remains stable at neutral or slightly alkaline pH.[10][11]
Unlike many lysosomal proteases that are confined within lysosomes due to stability issues, cathepsin S remains stable outside the lysosome, allowing it to function in extracellular processes. Immune cells, including macrophages and microglia, secrete cathepsin S in response to inflammatory mediators such as lipopolysaccharides, proinflammatory cytokines, and neutrophils. Cathepsin S is produced as a zymogen and activated through proteolytic processing. It retains some enzymatic activity even in the presence of 3M urea.
The activity of cathepsin S is tightly regulated by its endogenous inhibitor, cystatin C, which also plays a role in antigen presentation.Cystatin A andB have lower inhibitory activity compared to cystatin C.
Cathepsin S has been shown to be a significant prognostic factor for patients with type IVastrocytomas (glioblastoma multiforme), and its inhibition has shown to increase survival time.[12] This is because the cysteine enzyme can no longer act together with other proteases to break up the brain extracellular matrix.
Cathepsin S has a role innociception, including itch and gastrointestinal pain. The mechanism by which cathepsin S leads to itch and pain is consistent with the capacity of this cysteine protease to activate protease-activated receptors 2 and 4.[16][8]
Intumorigenesis, cathepsin S promotes tumor growth. Its expression can be triggered by proinflammatory factors secreted by tumor cells, contributing to cancer progression.
Cathepsin S expression and activity are upregulated in the skin ofpsoriasis patients. Although its definitive role in psoriasis pathology is not yet clear, cathepsin S has been shown to cleave and activate the psoriasis-associated proinflammatory cytokineIL-36γ.[17]
Synthetic inhibitors of cathepsin S participated in numerous preclinical studies for the immune disorders including rheumatoid arthritis. Currently, at least one of them participates in a clinical trial for psoriasis. LHVS (morpholinurea-leucine-homophenylalanine-vinylsulfone-phenyl) is the most extensively studied synthetic inhibitor of cathepsin S. IC50 of LHVS is about 5 nM. Inhibition of cathepsin S by LHVS has shown to be neuroprotective after traumatic brain injury.[18] The list of commercial inhibitors also includes paecilopeptin (acetyl-Leu-Val-CHO) and some others.
^Chapman HA, Riese RJ, Shi GP (1997). "Emerging roles for cysteine proteases in human biology".Annual Review of Physiology.59 (1):63–88.doi:10.1146/annurev.physiol.59.1.63.PMID9074757.
^Flannery T, McQuaid S, McGoohan C, McConnell RS, McGregor G, Mirakhur M, et al. (August 2006). "Cathepsin S expression: An independent prognostic factor in glioblastoma tumours--A pilot study".International Journal of Cancer.119 (4):854–860.doi:10.1002/ijc.21911.PMID16550604.
^Cheng XW, Huang Z, Kuzuya M, Okumura K, Murohara T (December 2011). "Cysteine protease cathepsins in atherosclerosis-based vascular disease and its complications".Hypertension.58 (6):978–986.doi:10.1161/HYPERTENSIONAHA.111.180935.PMID21986502.
^Liu J, Ma L, Yang J, Ren A, Sun Z, Yan G, et al. (June 2006). "Increased serum cathepsin S in patients with atherosclerosis and diabetes".Atherosclerosis.186 (2):411–419.doi:10.1016/j.atherosclerosis.2005.08.001.PMID16140306.
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