HGNC Approved Gene Symbol: CTSS
Cytogenetic location: 1q21.3 Genomic coordinates (GRCh38): 1:150,730,188-150,765,778 (from NCBI)
Cathepsin S (CTSS) belongs the family of lysosomal cysteine proteases. In macrophages and dendritic cells, it functions as a major endoprotease that cleaves the invariant chain (CD74; 142790) from the major histocompatibility complex (MHC) class II complex prior to antigen presentation. In addition to its role in antigen processing, CTSS can remodel the extracellular matrix in various tissues when secreted. Unlike other acidic lysosomal proteases, CTSS remains catalytically active and stable in neutral pH, allowing for its proteolytic activity when secreted (summary by Tjondrokoesoemo et al., 2016).
Alveolar macrophages express an elastase activity of acidic pH optimum inhibitable by cysteine protease inhibitors. It had been shown that the only previously known eukaryotic elastinolytic cysteine protease, cathepsin L (116880), could not completely account for this activity. In a search for additional cysteine proteases with elastinolytic activity, Shi et al. (1992) used low-degeneracy oligonucleotide primers based on regions of strong amino acid homology among the known cysteine proteases to screen reverse-transcribed human alveolar macrophage RNA for cysteine proteases by PCR. The screening turned up a cDNA sequence highly homologous to bovine cathepsin S. The recombinant enzyme was found to be elastinolytic. The relatively broad pH range of human cathepsin S activity suggested that it plays a significant role in the contact-dependent elastase activity of alveolar macrophages.
Northern blot analysis by Shi et al. (1994) showed that cathepsin S shows a restricted tissue distribution, with highest levels in spleen, heart, and lung. Immunostaining of lung tissue demonstrated detectable cathepsin S only in lung macrophages. The high level of expression in the spleen and in phagocytes suggested to Shi et al. (1994) that cathepsin S may have a specific function in immunity, perhaps related to antigen processing.
Shi et al. (1994) found that the structure of the cathepsin S gene is similar to that of cathepsin L through the first 5 exons, except that cathepsin S introns are substantially larger. In contrast to cathepsin B (116810), the cathepsin S gene contains only 2 Sp1 (189906) and at least 18 AP1 (see 165160) binding sites that potentially may be involved in regulation of the gene. The 5-prime flanking region also contains CA microsatellites. The presence of AP1 sites and CA microsatellites suggested that cathepsin S may be specifically regulated, a hypothesis that was supported by the results of Northern blot analysis.
By fluorescence in situ hybridization (FISH), Shi et al. (1994) mapped the CTSS gene to 1q21. Deussing et al. (1997) mapped Ctss to mouse chromosome 3. By FISH, Gelb et al. (1997) mapped the cathepsin K gene (601105) to 1q21 within 150 kb of CTSS.
Cathepsins S and L play prominent roles in the degradation of the MHC class II invariant chain (Ii, or CD74). In I-A(b) class II mice lacking the Ctss gene, failure to degrade Ii resulted in the accumulation of a class II-associated, 10-kD Ii fragment within endosomes, disrupting class II trafficking, peptide complex formation, and class II-restricted antigen presentation (Driessen et al., 1999). Riese et al. (2001) showed that I-A(b) class II haplotype mice lacking the Ctss gene had impaired NK1.1-positive T-cell selection and function. There were no overt defects in Cd4 (186940)-positive and Cd8 (see 186910)-positive T-cell populations. In Ctss -/- mice, thymic dendritic cells had defective presentation of the Cd1d (188410)-restricted antigen, the marine sponge glycosphingolipid alpha-galactosylceramide. Cd1d colocalized with Ii fragments and accumulated within endocytic dendritic cell compartments, impairing Cd1d trafficking. This dysfunction did not occur, however, in Ctss -/- mice of the I-A(k) class II haplotype. Riese et al. (2001) concluded that Cd1d function is critically linked to the processing of Ii, revealing that MHC class II haplotype and Ctss activity are regulators of NK T cells.
Tjondrokoesoemo et al. (2016) observed significant induction of Ctss expression in injured wildtype mouse muscle or muscle from mdx mice, a model of Duchenne muscular dystrophy (DMD; 310200). Deletion of Ctss in mdx mice resulted in protection from DMD pathogenesis, including reduced myofiber turnover and pathology, reduced fibrosis, and improved running capacity. Ctss deletion in mdx mice significantly increased myofiber sarcolemma membrane stability, with enhanced expression and membrane localization of utrophin (UTRN; 128240), intregrins (e.g., ITGA5; 135620), and beta-dystroglycan (128239), which anchor the membrane to the basal lamina and underlying cytoskeletal proteins. Transgenic mice overexpressing Ctss in skeletal muscle exhibited increased myofiber necrosis, muscle histopathology, and deficits similar to those of muscular dystrophy. Tjondrokoesoemo et al. (2016) concluded that CTSS induction during muscular dystrophy is a pathologic event that underlies disease pathogenesis.
Deussing, J., Roth, W., Rommerskirch, W., Wiederanders, B., von Figura, K., Peters, C. The genes of the lysosomal cysteine proteinases cathepsin B, H, L, and S map to different mouse chromosomes. Mammalian Genome 8: 241-245, 1997. [PubMed: 9096102] [Full Text: https://doi.org/10.1007/s003359900401]
Driessen, C., Bryant, R. A., Lennon-Dumenil, A. M., Villadangos, J. A., Bryant, P. W., Shi, G. P., Chapman, H. A., Ploegh, H. L. Cathepsin S controls the trafficking and maturation of MHC class II molecules in dendritic cells. J. Cell Biol. 147: 775-790, 1999. [PubMed: 10562280] [Full Text: https://doi.org/10.1083/jcb.147.4.775]
Gelb, B. D., Shi, G.-P., Heller, M., Weremowicz, S., Morton, C., Desnick, R. J., Chapman, H. A. Structure and chromosomal assignment of the human cathepsin K gene. Genomics 41: 258-262, 1997. [PubMed: 9143502] [Full Text: https://doi.org/10.1006/geno.1997.4631]
Riese, R. J., Shi, G.-P., Villadangos, J., Stetson, D., Driessen, C., Lennon-Dumenil, A.-M., Chu, C.-L., Naumov, Y., Behar, S. M., Ploegh, H., Locksley, R., Chapman, H. A. Regulation of CD1 function and NK1.1+ T cell selection and maturation by cathepsin S. Immunity 15: 909-919, 2001. [PubMed: 11754813] [Full Text: https://doi.org/10.1016/s1074-7613(01)00247-3]
Shi, G.-P., Munger, J. S., Meara, J. P., Rich, D. H., Chapman, H. A. Molecular cloning and expression of human alveolar macrophage cathepsin S, an elastinolytic cysteine protease. J. Biol. Chem. 267: 7258-7262, 1992. [PubMed: 1373132]
Shi, G.-P., Webb, A. C., Foster, K. E., Knoll, J. H. M., Lemere, C. A., Munger, J. S., Chapman, H. A. Human cathepsin S: chromosomal localization, gene structure, and tissue distribution. J. Biol. Chem. 269: 11530-11536, 1994. [PubMed: 8157683]
Tjondrokoesoemo, A., Schips, T. G., Sargent, M. A., Vanhoutte, D., Kanisicak, O., Prasad, V., Lin, S.-C. J., Maillet, M., Molkentin, J. D. Cathepsin S contributes to the pathogenesis of muscular dystrophy in mice. J. Biol. Chem. 291: 9920-9928, 2016. [PubMed: 26966179] [Full Text: https://doi.org/10.1074/jbc.M116.719054]