Disease relevance of CTSS

• The clinical significance of cathepsin S expression in human astrocytomas [1].
• The lysosomal cysteine protease, cathepsin S, is increased in Alzheimer's disease and Down syndrome brain. An immunocytochemical study [2].
• Antigen processing and presentation in human muscle: cathepsin S is critical for MHC class II expression and upregulated in inflammatory myopathies [3].
• Cathepsin S in tumours, regional lymph nodes and sera of patients with lung cancer: relation to prognosis [4].
• A clinical lower limb score correlated with the anterior (P = 0.03) and lateral (P = 0.04) column total scores and with the CTSS (P = 0.04) in the nine patients who had had both myelopathy related disability and all cord levels available [5].

High impact information on CTSS

• Purified cathepsin S, but not cathepsin B, H, or D, specifically digested li from alpha beta li trimers, generating alpha beta-CLIP complexes capable of binding exogenously added peptide in vitro [6].
• The cysteine protease cathepsin S is highly expressed in spleen, lymphocytes, monocytes, and other class II-positive cells, and is inducible with interferon-gamma [6].
• Thus, cathepsin S is essential in B cells for effective li proteolysis necessary to render class II molecules competent for binding peptides [6].
• SMC stimulated with the atheroma-associated cytokines IL-1beta or IFN-gamma secreted active cathepsin S and degraded substantial insoluble elastin (15-20 microg/10(6) cells/24 h) [7].
• Localization of cysteine protease, cathepsin S, to the surface of vascular smooth muscle cells by association with integrin alphanubeta3 [8].

Chemical compound and disease context of CTSS

• Proteolytic enzymes have been implicated in facilitating tumor cell invasion and the current study was designed to characterize the expression of the cysteine proteinase cathepsin S (CatS) in astrocytomas and examine its potential role in invasion [1].
• Furthermore, patients with acute (p=0.009) or previous myocardial infarction (p<0.02) or unstable angina pectoris (p<0.05) had elevated levels of cathepsin S after adjustment for smoking, creatinine, cystatin C, and serum glucose [9].
• Our objective was to characterize the effects of lipopolysaccharide (LPS) from Escherichia coli (E coli), Bacteroides fragilis, (B frag)and Fusobacterium nucleatum (F nuc)on the expression of pro-inflammatory cytokines and the elastin-degrading enzyme, cathepsin S, in human CSMC [10].

Biological context of CTSS

• The frequency of the CTSS -25A allele was 0.457 in Caucasians and 0.431 in Canadian Inuit. Because of the importance of the CTSS gene product in vascular matrix remodeling, this polymorphism may be useful in the study of associations with atherosclerosis and related phenotypes [11].
• This report documents that cathepsin S in human keratinocytes is selectively upregulated, in parallel to major histocompatibility complex class II molecules, in response to a pro-inflammatory cytokine [12].
• Cleavage between the Gly and Ser residues of the reactive site loop and detection of a stable SCCA1-cathepsin S complex by sodium dodecyl sulfate-polyacrylamide gel electrophoresis suggested that the serpin interacted with the cysteine proteinase in a manner similar to that observed for typical serpin-serine proteinase interactions [13].
• Interferon-gamma stimulation of primary keratinocytes and HaCaT cells resulted in a selective upregulation of the cathepsin S activity, the extent of which was very similar [12].
• Papain, and to a minor extent cathepsin H, hydrolyzed the propeptide of cathepsin S, leading to competition with the hydrolysis of the fluorogenic substrates in the respective assays [14].

Anatomical context of CTSS

• Cathepsin S activity is detectable in human keratinocytes and is selectively upregulated upon stimulation with interferon-gamma [12].
• In the expressing baby hamster kidney cells, human cathepsin S is transported to the lysosomes via the mannose 6-phosphate receptor pathway as shown by density gradient centrifugation, immunofluorescence, and detection of the 37-kDa cathepsin S precursor in the medium in the presence of NH4Cl [15].
• The relatively broad pH range of human cathepsin S activity suggests this enzyme may contribute to the contact-dependent elastase activity of live human alveolar macrophages [16].
• This cDNA predicts a 329-amino acid preprocathepsin with more than 50% identity to both human cathepsin S and cathepsin L and 94% identity to a rabbit cDNA, termed OC2, recently isolated from osteoclasts [17].
• Cysteine proteinase cathepsin S (Cat S) is expressed mainly in lymphatic tissues and has been characterised as a key enzyme in major histocompatibility complex class II (MHC-II) mediated antigen presentation [4].

Associations of CTSS with chemical compounds

• In contrast, cathepsin S preferred phenylalanine to valine in S2, but bound less tightly to the V10W cystatin variant [18].
• The NH2-terminal amino acid sequence of the mature polypeptide was confirmed by sequencing cathepsin S purified from human spleen [15].
• The replacement of Gly-133 in cathepsin S by an alanine residue that is normally found at this position in both cathepsin B and L results in a pattern of specificity toward hydrophobic residues in P2 that is very similar to that of cathepsin B and L [19].
• Radiosequencing of A beta secreted by cathepsin S-expressing cells revealed that a previously unreported variant beginning at Met -1 (relative to the most common A beta N-terminus, Asp -1) accounted for most of the increase in A beta secretion [20].
• Epoxy succinate peptide derivatives, CLIK-066, 088, 112, 121, 148, 181, 185 and 187, are typical specific inhibitors for cathepsin L. Aldehyde derivatives CLIK-060 and CLIK-164 showed specific inhibition against cathepsin S and cathepsin K, respectively [21].

Regulatory relationships of CTSS

• The propeptide of cathepsin S strongly inhibited cathepsin S (Ki = 0.27 nM) and the two cathepsin L species (Ki = 0.36 nM) at neutral pH [14].
• Expression and upregulation of cathepsin S and other early molecules required for antigen presentation in activated hepatic stellate cells upon IFN-gamma treatment [22].
• A time course analysis revealed that 10 ng/ml of TNF-alpha induced cathepsin S, MMP-1, -3, and -9 mRNA expression with the maximal response observed after 24-48 hours [23].
• In contrast, neither RA- nor OA-derived fibroblasts expressed detectable levels of cathepsin S [24].

Other interactions of CTSS

• The inhibitory properties displayed by cystatin D suggest that it has a function in saliva as inhibitor of either endogenous or exogenous enzymes with cathepsin S- or H-like properties [25].
• The latter variant proved to be valuable for discriminating between cathepsin L and cathepsin S (Ki 2.4 and 190 pM respectively) [18].
• In contrast, for cathepsin S inhibition these interactions are of lesser significance, as reflected by a Ki value of 10(-8) M for the cystatin C variant devoid of Arg-8, Leu-9, Val-10, and Trp-106 side chains [26].
• As with cathepsin B, the activities of the Phe-205-->Glu single and the Gly-133-->Ala/Phen-205-->Glu double mutants of cathepsin S toward the dibasic substrate is modulated by an additional ionizable group with a pKa of 5.7 [19].
• Fluorescence titrations showed that high-molecular-weight kininogen binds two molecules of papain, cruzipain and cathepsin S with high affinity [27].

Analytical, diagnostic and therapeutic context of CTSS

• 0. Labeling of HAM with the active site probe revealed these cells express a 28-kDa cysteine protease, and Northern blot analysis revealed the presence of a approximately 1.7-kilobase cathepsin S mRNA [16].
• Molecular cloning and expression of human alveolar macrophage cathepsin S, an elastinolytic cysteine protease [16].
• The S2 binding site specificity of this enzyme has been altered to mimic that of cathepsin B or L by the application of site-directed mutagenesis at these latter three positions in the cathepsin S sequence [19].
• A beta secretion was assessed by immunoprecipitation and ELISA and found to be increased approximately 2-fold following cathepsin S expression, but to be unchanged (cathepsins B, L) or decreased (cathepsin D) in the other double transfectants [20].
• Cathepsin K was mapped to chromosome 1q21 by fluorescence in situ hybridization and found to reside within 150 kb of an evolutionarily related cysteine protease, cathepsin S [28].

References