Cathepsin S

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Cathepsin S
Protein CTSS PDB 1glo.png
PDB rendering based on 1glo.
Available structures
PDB Ortholog search: PDBe, RCSB
Identifiers
Symbols CTSS ; FLJ50259; MGC3886
External IDs OMIM116845 MGI107341 HomoloGene20867 ChEMBL: 2954 GeneCards: CTSS Gene
EC number 3.4.22.27
RNA expression pattern
PBB GE CTSS 202902 s at tn.png
PBB GE CTSS 202901 x at tn.png
More reference expression data
Orthologs
Species Human Mouse
Entrez 1520 13040
Ensembl ENSG00000163131 ENSMUSG00000038642
UniProt P25774 O70370
RefSeq (mRNA) NM_001199739 NM_001267695
RefSeq (protein) NP_001186668 NP_001254624
Location (UCSC) Chr 1:
150.7 – 150.74 Mb
Chr 3:
95.53 – 95.56 Mb
PubMed search [1] [2]

Cathepsin S, also known as CTSS, is a protein that in humans is encoded by the CTSS gene.[1] Transcript variants utilizing alternative polyadenylation signals exist for this gene.[1]

The protein encoded by this gene, a member of the peptidase C1 family, is a lysosomal cysteine protease that may participate in the degradation of antigenic proteins to peptides for presentation on MHC class II molecules. The encoded protein can function as an elastase over a broad pH range in alveolar macrophages. Transcript variants utilizing alternative polyadenylation signals exist for this gene.[1]

Function[edit]

Cathepsin S is a lysosomal enzyme that belongs to the papain family of cysteine proteases. This protein is expressed by antigen presenting cells including macrophages, B-lymphocytes, dendritic cells and microglia. Moreover, cathepsin S is expressed in some epithelial cells. In contrast, cortical thymic epithelial cells do not express cathepsin S. Normal epidermal keratinocytes do not express cathepsin S. However, level of cathepsin S is elevated in psoriatic keratinocytes due to stimulation by proinflammatory factors.

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.

Most of other lysosomal proteases are trapped inside the lysosome due to a problem with their stability. Unlike them, cathepsin S remains stable and it has a physiological role outside the lysosome. Immune cells, such as macrophages and microglia secrete cathepsin S in response to inflammatory mediators such as lipopolysaccharides, proinflammatory cytokines and neutrophils. In vitro, cathepsin S retains some enzyme activity in the presence of 3M urea. Moreover, cathepsin S does not necessarily require processing. Folding the expressed fusion protein gives an active enzyme.

The activity of cathepsin S is tightly regulated by its endogenous inhibitor, cystatin C, which also has a role in antigen presentation. 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[edit]

This enzyme has a critical role in antigen presentation. In general, major histocompatibility complex, class II selects small peptide fragments for presentation on the surface of the antigen-presenting immune cells. Particularly, cathepsin S participates in a degradation of polypeptide Li that prevents loading the antigen into the complex. This degradation occurs in the lysosome and it is a part of normal MHC II folding process. Chronologically, action of cathepsin S follows two cleavages performed by 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 cathepsin F.

Role in degradation of ECM[edit]

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

In tumorogenesis, cathepsin S promotes a tumor growth.

Nociception[edit]

Cathepsin S has a role in nociception.

Cathepsin S inhibitors[edit]

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

Clinical significance[edit]

Cathepsin S has been shown to be a significant prognostic factor for patients with type IV 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.[2]

See also[edit]

References[edit]

Further reading[edit]

External links[edit]

  • The MEROPS online database for peptidases and their inhibitors: C01.034