Alternative titles; symbols
Other entities represented in this entry:
HGNC Approved Gene Symbol: CTSB
Cytogenetic location: 8p23.1 Genomic coordinates (GRCh38): 8:11,842,524-11,868,087 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 8p23.1 | Keratolytic winter erythema | 148370 | Autosomal dominant | 4 |
Murnane (1985) pointed out amino acid sequence homology between HRAS p21 (190020) and cathepsin B.
Chan et al. (1986) cloned preprocathepsin B from hepatoma and kidney cDNA libraries. The deduced 339-amino acid preprocathepsin B contains a 17-residue N-terminal prepeptide followed by a 62-residue propeptide, 254 residues that are in the mature (single-chain) cathepsin B, and a 6-residue C-terminal extension. Human, mouse, and rat procathepsin B share at least 68% sequence identity.
Moin et al. (1992) purified 3 forms of cathepsin B from normal human liver and several human tumor tissues. SDS-PAGE detected 2 forms of 25 and 26 kD that appeared as a doublet and a third form of about 30 kD. The doublet was associated with the highest cathepsin B activity. N-terminal sequencing revealed that the 25- and 26-kD forms represent the heavy chain of the mature double-chain form of cathepsin B. Endoglycosidase treatment converted the 26-kD form into the 25-kD form, suggesting that cathepsin B exists as both glycosylated and unglycosylated forms. N-terminal sequencing indicated that the 30-kD protein was the single-chain form. Using several biochemical and immunologic criteria, Moin et al. (1992) determined that the tumor and normal liver forms of cathepsin B were similar in all characteristics examined.
Tam et al. (1994) isolated 2 CTSB cDNAs from a normal human embryonic fibroblast cDNA library. These clones have a 10-bp insertion in the 3-prime untranslated region (UTR) compared with the CTSB sequence reported by Chan et al. (1986). The insertion may allow the formation of a stable stem-loop structure. One of the clones reported by Tam et al. (1994) also has an extension of about 1 kb in the 3-prime UTR. Northern blot analysis using probes unique to the 3-prime UTR extension detected 4.0- and 1.7-kb CTSB transcripts, but not the major 2.2-kb transcript.
Berquin et al. (1995) stated that the CTSB gene contains 12 exons. They identified 2 additional alternatively splices exons, which they designated 2a and 2b, between exons 2 and 3 in the 5-prime UTR of the CTSB gene. All of the exons of the 5-prime UTR could be alternatively spliced to produce several transcript species. In addition, there are at least 3 upstream translation initiation codons. Berquin et al. (1995) determined that the CTSB gene spans nearly 27 kb, although they suggested that it may be larger.
Wang et al. (1987) assigned the CTSB gene to chromosome 8p22 by means of a cDNA probe used in Southern blot analysis of somatic cell hybrids and in situ hybridization. Fong et al. (1992) mapped CTSB to 8p23.1-p22 by 3 independent methods: analysis of human-hamster somatic cell hybrid DNA by PCR, comparison of hybridization signals to cathepsin B in interphase nuclei of normal fibroblasts and fibroblasts with a chromosome 8 deletion, and fluorescence in situ hybridization.
Deussing et al. (1997) mapped the Ctsb gene to mouse chromosome 14 and localized a related sequence to chromosome 2.
Esch et al. (1990) demonstrated cleavage of the amyloid beta peptide during constitutive processing of its precursor (APP; 104760). Cleavage occurs in the interior of the amyloid peptide sequence, thereby precluding formation and deposition of the APP protein. Esch et al. (1990) suggested that a genetic defect in this processing mechanism might be a basis of Alzheimer disease (104300). Tagawa et al. (1991) demonstrated that APP secretase is identical to cathepsin B.
By RT-PCR and primer extension assays, Berquin et al. (1995) found that CTSB mRNA species differed among tissues and between a glioblastoma sample and a cell line derived from it. Two alternative exons, exons 2a and 2b, were detected more frequently in tumor samples than in matched normal tissues.
Antigen presentation by major histocompatibility complex (MHC) class II molecules requires the participation of different proteases in the endocytic route to degrade endocytosed antigens as well as the MHC class II-associated invariant chain. Only cathepsin S (116845) appears to be essential for complete destruction of the invariant chain. Degradation of antigens themselves in vitro and experiments using protease inhibitors suggested that cathepsin B and cathepsin D (116840), 2 major cysteine and aspartyl proteases, respectively, are involved in antigen degradation. Deussing et al. (1998) analyzed the antigen-presenting properties of cells derived from mice deficient in either cathepsin B or cathepsin D and found that the overall capacity of the antigen-presenting cells deficient in either cathepsin was unaffected. Degradation of the invariant chain proceeded normally in both classes of cells. Deussing et al. (1998) concluded that neither cathepsin B nor cathepsin D is essential for MHC class II-mediated antigen presentation.
CTSB is overexpressed in tumors of the lung, prostate, colon, breast, and stomach. Hughes et al. (1998) found an amplicon at 8p23-p22 that resulted in CTSB overexpression in esophageal adenocarcinoma. Of the potentially coamplified genes that are known to map to this region, they found that Southern blot analysis of 66 esophageal adenocarcinomas demonstrated only CTSB and the gene for farnesyldiphosphate farnesyltransferase (FDFT1; 184420) to be the only ones consistently amplified in 8 (12.1%) of the tumors. Northern blot analysis showed overexpression of CTSB and FDFT1 mRNA in all 6 of the amplified esophageal adenocarcinomas analyzed. CTSB mRNA overexpression also was present in 2 of 6 nonamplified tumors analyzed. However, FDFT1 mRNA overexpression without amplification was not observed. Abundant extracellular expression of CTSB protein was found in 29 of 40 (72.5%) of esophageal adenocarcinoma specimens by use of immunohistochemical analysis. The findings were thought to support an important role for CTSB in esophageal adenocarcinoma and possibly in other tumors.
Guicciardi et al. (2000) determined that Ctsb accumulated in the cytosol of mouse hepatocytes and rat hepatoma cells exposed to TNFA (191160) and that it contributed to TNFA-induced apoptosis. Using cell-free systems, they showed that caspase-8 (601763) caused release of active Ctsb from purified lysosomes and that Ctsb, in turn, increased cytosol-induced release of cytochrome c from mitochondria. TNFA-induced apoptosis was markedly diminished in hepatocytes isolated from Ctsb-null mice.
By yeast 2-hybrid screening of a human fetal liver cDNA library, Liu et al. (2006) found that SB1 (SHKBP1; 617322) interacted with lysosomal CTSB. Protein pull-down analysis of in vitro-translated proteins and coimmunoprecipitation analysis of cotransfected HeLa cells confirmed interaction between SB1 and CTSB. Overexpression of SB1 protected OV-90 cells from TNF-induced apoptosis, which involves CTSB-dependent lysosome rupture. However, SB1 overexpression did not alter CTSB activity against a synthetic substrate in OV-90 cell lysates.
By immunogold electron microscopy, Kukor et al. (2002) determined that CTSB is abundant in the secretory compartment of the exocrine pancreas. Pro-CTSB and mature CTSB were secreted together with trypsinogen (276000) and active trypsin into the pancreatic juice of patients with sporadic or hereditary pancreatitis (167800). CTSB activated trypsinogen in vitro, but it appeared unlikely that CTSB contributes to hereditary pancreatitis.
Using selective protease inhibitors in African green monkey kidney cells and protease-deficient mouse cell lines, Chandran et al. (2005) identified an essential role for Catb and an accessory role for Catl (CTSL; 116880) in the entry of vesicular stomatitis virus particles pseudotyped with Ebola virus glycoprotein. They proposed that CATB and CATL are part of a multistep mechanism contributing to Ebola virus infection and that cathepsin inhibitors that diminish viral multiplication may have a role in antiviral therapy.
Using proteomic analysis, Moon et al. (2016) found that levels of Ctsb were elevated in conditioned medium from rat skeletal muscle cell cultures treated with the AMPK (see 602739) agonist AICAR to mimic the effects of exercise in vitro. Running increased Ctsb levels in mouse gastrocnemius muscle and plasma. Moreover, running increased hippocampal Ctsb mRNA, adult hippocampal neurogenesis, and spatial memory in mice. Application of recombinant Ctsb to adult rat hippocampal progenitor cells enhanced expression of Bdnf (113505) and Dcx (300121), which are involved in neurogenesis, through a mechanism dependent on increased hippocampal expression of the multifunctional protein p11 (S100A10; 114085). Mice lacking Ctsb showed deficits in spatial memory, adult hippocampal neurogenesis, dentate granule cell physiology, and hippocampal p11 levels compared with wildtype mice. In rhesus monkeys and humans, treadmill exercise elevated CTSB levels in plasma. Changes in CTSB levels in humans correlated with fitness and hippocampus-dependent memory function. Moon et al. (2016) concluded that CTSB is a muscle secretory factor that mediates the cognitive and neurogenic benefits of exercise.
Keratolytic Winter Erythema
In 7 South African families (A, B, C, F, G, H, and I) with keratolytic winter erythema (KWE; 148370), Ngcungcu et al. (2017) identified a noncoding 7.67-kb tandem duplication on chromosome 8 (chr8:11,729,286-11,736,955, GRCh37) that segregated with disease and was not found in 127 controls. In 2 Norwegian families (D and E) with KWE, they identified a 15.93-kb tandem duplication (chr8:11,734,333-11,750,263, GRCh37) that segregated with disease and overlapped the South African duplication, as well as a 95-bp triplication between the tandemly duplicated regions. Both duplications were located upstream of the CTSB gene, and the 2.62-kb region of overlap (chr8:11,734,333-11,736,955) was found to encompass an active enhancer element in keratinocytes. Enhancer activity was associated with increased expression of CTSB during keratinocyte differentiation, consistent with histone marker data in multiple cell lines, and RNAPII interaction loops were detected between the enhancer and the CTSB promoter. In addition, QT-PCR of nonlesioned palmar epidermis showed significantly higher relative expression of CTSB in patients relative to controls, and immunohistochemistry showed stronger CTSB staining in the stratum granulosum of patients as well. Ngcungcu et al. (2017) concluded that the KWE phenotype is caused by dysregulated expression of CTSB in the epidermis.
Associations Pending Confirmation
Mahurkar et al. (2006) found an association between the val26 allele of a leu26-to-val polymorphism (rs12338) in the CTSB gene in patients with tropical calcific pancreatitis (TCP; 608189); the association appeared to be independent of SPINK1 (167790) mutation status, suggesting that val26 may act as a susceptibility allele in the pathogenesis of TCP.
Berquin, I. M., Cao, L., Fong, D., Sloane, B. F. Identification of two new exons and multiple transcription start points in the 5-prime-untranslated region of the human cathepsin-B-encoding gene. Gene 159: 143-149, 1995. [PubMed: 7622042] [Full Text: https://doi.org/10.1016/0378-1119(95)00072-e]
Chan, S. J., San Segundo, B., McCormick, M. B., Steiner, D. F. Nucleotide and predicted amino acid sequences of cloned human and mouse preprocathepsin B cDNAs. Proc. Nat. Acad. Sci. 83: 7721-7725, 1986. [PubMed: 3463996] [Full Text: https://doi.org/10.1073/pnas.83.20.7721]
Chandran, K., Sullivan, N. J., Felbor, U., Whelan, S. P., Cunningham, J. M. Endosomal proteolysis of the Ebola virus glycoprotein is necessary for infection. Science 308: 1643-1645, 2005. [PubMed: 15831716] [Full Text: https://doi.org/10.1126/science.1110656]
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]
Deussing, J., Roth, W., Saftig, P., Peters, C., Ploegh, H. L., Villadangos, J. A. Cathepsins B and D are dispensable for major histocompatibility complex class II-mediated antigen presentation. Proc. Nat. Acad. Sci. 95: 4516-4521, 1998. [PubMed: 9539769] [Full Text: https://doi.org/10.1073/pnas.95.8.4516]
Esch, F. S., Keim, P. S., Beattie, E. C., Blacher, R. W., Culwell, A. R., Oltersdorf, T., McClure, D., Ward, P. J. Cleavage of amyloid beta peptide during constitutive processing of its precursor. Science 248: 1122-1124, 1990. [PubMed: 2111583] [Full Text: https://doi.org/10.1126/science.2111583]
Fong, D., Chan, M. M.-Y., Hsieh, W.-T., Menninger, J. C., Ward, D. C. Confirmation of the human cathepsin B gene (CTSB) assignment to chromosome 8. Hum. Genet. 89: 10-12, 1992. [PubMed: 1577456] [Full Text: https://doi.org/10.1007/BF00207033]
Guicciardi, M. E., Deussing, J., Miyoshi, H., Bronk, S. F., Svingen, P. A., Peters, C., Kaufmann, S. H., Gores, G. J. Cathepsin B contributes to TNF-alpha-mediated hepatocyte apoptosis by promoting mitochondrial release of cytochrome c. J. Clin. Invest. 106: 1127-1137, 2000. [PubMed: 11067865] [Full Text: https://doi.org/10.1172/JCI9914]
Hughes, S. J., Glover, T. W., Zhu, X.-X., Kuick, R., Thoraval, D., Orringer, M. B., Beer, D. G., Hanash, S. A novel amplicon at 8p22-23 results in overexpression of cathepsin B in esophageal adenocarcinoma. Proc. Nat. Acad. Sci. 95: 12410-12415, 1998. [PubMed: 9770500] [Full Text: https://doi.org/10.1073/pnas.95.21.12410]
Kukor, Z., Mayerle, J., Kruger, B., Toth, M., Steed, P. M., Halangk, W., Lerch, M. M., Sahin-Toth, M. Presence of cathepsin B in the human pancreatic secretory pathway and its role in trypsinogen activation during hereditary pancreatitis. J. Biol. Chem. 277: 21389-21396, 2002. [PubMed: 11932257] [Full Text: https://doi.org/10.1074/jbc.M200878200]
Liu, J.-P., Liu, N.-S., Yuan, H.-Y., Guo, Q., Lu, H., Li, Y.-Y. Human homologue of SETA binding protein 1 interacts with cathepsin B and participates in TNF-induced apoptosis in ovarian cancer cells. Molec. Cell. Biochem. 292: 189-195, 2006. [PubMed: 16733801] [Full Text: https://doi.org/10.1007/s11010-006-9214-7]
Mahurkar, S., Idris, M. M., Reddy, D. N., Bhaskar, S., Rao, G. V., Thomas, V., Singh, L., Chandak, G. R. Association of cathepsin B gene polymorphisms with tropical calcific pancreatitis. Gut 55: 1270-1275, 2006. [PubMed: 16492714] [Full Text: https://doi.org/10.1136/gut.2005.087403]
Moin, K., Day, N. A., Sameni, M., Hasnain, S., Hirama, T., Sloane, B. F. Human tumour cathepsin B: comparison with normal liver cathepsin B. Biochem. J. 285: 427-434, 1992. [PubMed: 1637335] [Full Text: https://doi.org/10.1042/bj2850427]
Moon, H. Y., Becke, A., Berron, D., Becker, B., Sah, N., Benoni, G., Janke, E., Lubejko, S. T., Greig, N. H., Mattison, J. A., Duzel, E., van Praag, H. Running-induced systemic cathepsin B secretion is associated with memory function. Cell Metab. 24: 332-340, 2016. [PubMed: 27345423] [Full Text: https://doi.org/10.1016/j.cmet.2016.05.025]
Murnane, M. J. Cathepsin B-like thiol proteases: distant amino acid sequence homology to H-RAS p21. (Abstract) Am. J. Hum. Genet. 37: A33 only, 1985.
Ngcungcu, T., Oti, M., Sitek, J. C., Haukanes, B. I., Linghu, B., Bruccoleri, R., Stokowy, T., Oakeley, E. J., Yang, F., Zhu, J., Sultan, M., Schalwijk, J., and 17 others. Duplicated enhancer region increases expression of CTSB and segregates with keratolytic winter erythema in South African and Norwegian families. Am. J. Hum. Genet. 100: 737-750, 2017. [PubMed: 28457472] [Full Text: https://doi.org/10.1016/j.ajhg.2017.03.012]
Tagawa, K., Kunishita, T., Maruyama, K., Yoshikawa, K., Kominami, E., Tsuchiya, T., Suzuki, K., Tabira, T., Sugita, H., Ishiura, S. Alzheimer's disease amyloid beta-clipping enzyme (APP secretase): identification, purification, and characterization of the enzyme. Biochem. Biophys. Res. Commun. 177: 377-387, 1991. [PubMed: 1645961] [Full Text: https://doi.org/10.1016/0006-291x(91)91994-n]
Tam, S. W., Cote-Paulino, L. R., Peak, D. A., Sheahan, K., Murname, M. J. Human cathepsin B-encoding cDNAs: sequence variations in the 3-prime-untranslated region. Gene 139: 171-176, 1994. [PubMed: 7509303] [Full Text: https://doi.org/10.1016/0378-1119(94)90751-x]
Wang, X., Chan, S. J., Eddy, R. L., Byers, M. G., Fukushima, Y., Henry, W. M., Haley, L. L., Steiner, D. F., Shows, T. B. Chromosome assignment of cathepsin B (CTSB) to 8p22 and cathepsin H (CTSH) to 15q24-q25. (Abstract) Cytogenet. Cell Genet. 46: 710-711, 1987.