Cathepsin S

Cathepsin S, also known as CTSS, is a is_associated_with::protein that in humans is encoded by the CTSS is_associated_with::gene. Transcript variants utilizing alternative polyadenylation signals exist for this gene.

The protein encoded by this gene, a member of the peptidase C1 family, is a lysosomal is_associated_with::cysteine protease that may participate in the degradation of antigenic proteins to peptides for presentation on is_associated_with::MHC class II molecules. The encoded protein can function as an is_associated_with::elastase over a broad pH range in alveolar is_associated_with::macrophages. Transcript variants utilizing alternative polyadenylation signals exist for this gene.

Function
Cathepsin S is a lysosomal enzyme that belongs to the is_associated_with::papain family of is_associated_with::cysteine proteases. While a role in antigen presentation has long been recognized, it is now understood that cathepsin S has a role in itch and pain, or nociception. The nociceptive activity results from cathepsin S functioning as a signaling molecule via activation of protease-activated receptors 2 and 4 members of the G-protein coupled receptor family.

Cathepsin S is expressed by antigen presenting cells including is_associated_with::macrophages, is_associated_with::B-lymphocytes, is_associated_with::dendritic cells and is_associated_with::microglia. Cathepsin S is expressed by some is_associated_with::epithelial cells. Its expression is markedly increased in human keratinocytes following stimulation with interferon-gamma and its expression is elevated in is_associated_with::psoriatic is_associated_with::keratinocytes due to stimulation by proinflammatory factors. In contrast, cortical thymic epithelial cells do not express cathepsin S.

While pH optima of many lysosomal proteases are acidic, cathepsin S is an exception. This enzyme remains catalytically active under the neutral pH and has pH optimum between the pH values 6.0 and 7.5. Many lysosomal proteases are trapped inside the lysosome due to a problem with their stability. In contrast, cathepsin S remains stable and has a physiological role outside the lysosome. Immune cells, including macrophages and microglia, secrete cathepsin S in response to inflammatory mediators including lipopolysaccharides, proinflammatory cytokines and neutrophils. In vitro, cathepsin S retains some enzyme activity in the presence of 3M urea. Cathepsin S is produced as a zymogen and is activated by processing.

The activity of cathepsin S is tightly regulated by its endogenous inhibitor, cystatin C, which also has a role in antigen presentation. is_associated_with::Cystatin A and B have a lower activity compared to cystatin C.

The active cleavage sites -(-Val-Val-Arg-)- of cathepsin S are supposed to have at least two amino acids surrounding it from each side.

While lysosomal proteases terminally degrade proteins in lysosomes, cathepsin S has own distinctive physiological role.

Role in antigen presentation
This enzyme has a critical role in is_associated_with::antigen presentation. Major histocompatibility complex class II molecules interact with small peptide fragments for presentation on the surface of antigen-presenting immune cells. Cathepsin S participates in the degradation of the invariant or Ii chain that prevents loading the antigen into the complex. This degradation occurs in the lysosome. Chronologically, action of cathepsin S follows two cleavages performed by is_associated_with::aspartyl proteases. Cathepsin S cleaves the remaining fragment of Ii (IiP1) and leaves a small part of Ii known as CLIP which stays directly associated with the complex.

Proteolytic degradation of Ii is important since it facilitates dissociation of CLIP from MHC II and then, complex can load the selected antigen. After loading the antigen, MHC II molecule moves to the cell surface. Thus, we can speculate that overexpression of cathepsin S may lead to premature degradation of Ii, occasional loading of MHC II and an autoimmune attack. Contrary, inhibition of cathepsin S will lead to a delay in degradation of Ii and loading the antigen into MHC II as well as inappropriate presence of uncleaved Li-fragments in MHC II on the cell surface. It will impair and weaken the immune response. For instance, this kind of MHC II will not be very efficient to induce proliferation of T-cells.

In macrophages, cathepsin S can be replaced by is_associated_with::cathepsin F.

Role in degradation of ECM
Secreted cathepsin S cleaves some is_associated_with::extracellular matrix (ECM) proteins. Cathepsin S may be considered the most potent elastase known. The list of proposed cathepsin S substrates includes is_associated_with::laminin, fibronectin elastin, is_associated_with::osteocalcin and some is_associated_with::collagens. It also cleaves is_associated_with::chondroitin sulfate, is_associated_with::heparan sulfate and is_associated_with::proteoglycans of the is_associated_with::basal membrane. Cathepsin S plays an active role in blood vessels permeability and is_associated_with::angiogenesis due to its elastolytic and collagenolytic activities. For instance, cleavage of laminin-5 by cathepsin S leads to generation of proangiogenic peptides. The expression of cathepsin S can be triggered by proinflammatory factors secreted by tumor cells.

In is_associated_with::tumorogenesis, cathepsin S promotes a tumor growth.

Nociception
Cathepsin S has a role in is_associated_with::nociception, 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 two and four.

Cathepsin S inhibitors
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. The list of commercial inhibitors also includes paecilopeptin (acetyl-Leu-Val-CHO) and some others.

Clinical significance
Cathepsin S has been shown to be a significant prognostic factor for patients with type IV is_associated_with::astrocytomas (glioblastoma multiforme), and its inhibition has shown improvement in survival time by mean average 5 months. This is because the cysteine enzyme can no longer act together with other proteases to break up the brain extracellular matrix. So the spread of the tumor is halted. Scientists have just announced that this enzyme predicts death, as it has been shown to be associated with both heart disease and cancer.