PDB rendering based on 1glo.
|External IDs||ChEMBL: GeneCards:|
|RNA expression pattern|
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.
|This section does not cite any references or sources. (April 2012)|
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 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 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
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.
Cathepsin S has a role in nociception.
Cathepsin S inhibitors
|This section does not cite any references or sources. (April 2012)|
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.
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.
- "Entrez Gene: CTSS cathepsin S".
- Time. 31 August 2011 http://healthland.time.com/2011/08/31/a-blood-test-to-predict-death-it-could-be-possible/?hpt=hp_t2
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- Shi GP, Munger JS, Meara JP, et al. (1992). "Molecular cloning and expression of human alveolar macrophage cathepsin S, an elastinolytic cysteine protease.". J. Biol. Chem. 267 (11): 7258–62. PMID 1373132.
- Wiederanders B, Brömme D, Kirschke H, et al. (1992). "Phylogenetic conservation of cysteine proteinases. Cloning and expression of a cDNA coding for human cathepsin S.". J. Biol. Chem. 267 (19): 13708–13. PMID 1377692.
- Ritonja A, Colić A, Dolenc I, et al. (1991). "The complete amino acid sequence of bovine cathepsin S and a partial sequence of bovine cathepsin L.". FEBS Lett. 283 (2): 329–31. doi:10.1016/0014-5793(91)80620-I. PMID 2044774.
- Munger JS, Haass C, Lemere CA, et al. (1995). "Lysosomal processing of amyloid precursor protein to A beta peptides: a distinct role for cathepsin S.". Biochem. J. 311 (1): 299–305. PMC 1136152. PMID 7575468.
- Lemere CA, Munger JS, Shi GP, et al. (1995). "The lysosomal cysteine protease, cathepsin S, is increased in Alzheimer's disease and Down syndrome brain. An immunocytochemical study.". Am. J. Pathol. 146 (4): 848–60. PMC 1869262. PMID 7717452.
- Hall A, Håkansson K, Mason RW, et al. (1995). "Structural basis for the biological specificity of cystatin C. Identification of leucine 9 in the N-terminal binding region as a selectivity-conferring residue in the inhibition of mammalian cysteine peptidases.". J. Biol. Chem. 270 (10): 5115–21. doi:10.1074/jbc.270.10.5115. PMID 7890620.
- Balbín M, Hall A, Grubb A, et al. (1994). "Structural and functional characterization of two allelic variants of human cystatin D sharing a characteristic inhibition spectrum against mammalian cysteine proteinases.". J. Biol. Chem. 269 (37): 23156–62. PMID 8083219.
- Shi GP, Webb AC, Foster KE, et al. (1994). "Human cathepsin S: chromosomal localization, gene structure, and tissue distribution.". J. Biol. Chem. 269 (15): 11530–6. PMID 8157683.
- Turk B, Stoka V, Turk V, et al. (1996). "High-molecular-weight kininogen binds two molecules of cysteine proteinases with different rate constants.". FEBS Lett. 391 (1–2): 109–12. doi:10.1016/0014-5793(96)00611-4. PMID 8706894.
- Baumgrass R, Williamson MK, Price PA (1997). "Identification of peptide fragments generated by digestion of bovine and human osteocalcin with the lysosomal proteinases cathepsin B, D, L, H, and S". J. Bone Miner. Res. 12 (3): 447–55. doi:10.1359/jbmr.19220.127.116.117. PMID 9076588.
- Würl P, Taubert H, Meye A, et al. (1997). "Immunohistochemical and clinical evaluation of cathepsin expression in soft tissue sarcomas". Virchows Arch. 430 (3): 221–5. doi:10.1007/BF01324805. PMID 9099979.
- Gelb BD, Shi GP, Heller M, et al. (1997). "Structure and chromosomal assignment of the human cathepsin K gene". Genomics 41 (2): 258–62. doi:10.1006/geno.1997.4631. PMID 9143502.
- Baldassare JJ, Henderson PA, Tarver A, Fisher GJ (1997). "Thrombin activation of human platelets dissociates a complex containing gelsolin and actin from phosphatidylinositide-specific phospholipase Cgamma1". Biochem. J. 324 (1): 283–7. PMC 1218428. PMID 9164868.
- Nissler K, Kreusch S, Rommerskirch W, et al. (1998). "Sorting of non-glycosylated human procathepsin S in mammalian cells". Biol. Chem. 379 (2): 219–24. doi:10.1515/bchm.1998.379.2.219. PMID 9524075.
- Claus V, Jahraus A, Tjelle T, et al. (1998). "Lysosomal enzyme trafficking between phagosomes, endosomes, and lysosomes in J774 macrophages. Enrichment of cathepsin H in early endosomes". J. Biol. Chem. 273 (16): 9842–51. doi:10.1074/jbc.273.16.9842. PMID 9545324.
- Schick C, Pemberton PA, Shi GP, et al. (1998). "Cross-class inhibition of the cysteine proteinases cathepsins K, L, and S by the serpin squamous cell carcinoma antigen 1: a kinetic analysis". Biochemistry 37 (15): 5258–66. doi:10.1021/bi972521d. PMID 9548757.
- Fengler A, Brandt W (1999). "Three-dimensional structures of the cysteine proteases cathepsins K and S deduced by knowledge-based modelling and active site characteristics". Protein Eng. 11 (11): 1007–13. doi:10.1093/protein/11.11.1007. PMID 9876921.
- Söderström M, Salminen H, Glumoff V, et al. (1999). "Cathepsin expression during skeletal development". Biochim. Biophys. Acta 1446 (1–2): 35–46. doi:10.1016/S0167-4781(99)00068-8. PMID 10395917.
- Cao H, Hegele RA (2000). "Human cathepsin S gene (CTSS) promoter -25G/A polymorphism". J. Hum. Genet. 45 (2): 94–5. doi:10.1007/s100380050019. PMID 10721671.
- Luke C, Schick C, Tsu C, et al. (2000). "Simple modifications of the serpin reactive site loop convert SCCA2 into a cysteine proteinase inhibitor: a critical role for the P3' proline in facilitating RSL cleavage". Biochemistry 39 (24): 7081–91. doi:10.1021/bi000050g. PMID 10852705.