Cathepsin B

Cathepsin B belongs to a family of lysosomal cysteine proteases and plays an important role in intracellular proteolysis.[5] In humans, cathepsin B is encoded by the CTSB gene.[6][7] Cathepsin B is upregulated in certain cancers, in pre-malignant lesions, and in various other pathological conditions.[8][9][10][11]

For the Canadian agency, see Transportation Safety Board of Canada.
CTSB
Available structures
PDBOrtholog search: PDBe RCSB
Identifiers
AliasesCTSB, APPS, CPSB, cathepsin B, RECEUP
External IDsOMIM: 116810 MGI: 88561 HomoloGene: 37550 GeneCards: CTSB
Gene location (Human)
Chr.Chromosome 8 (human)[1]
Band8p23.1Start11,842,524 bp[1]
End11,869,448 bp[1]
RNA expression pattern




More reference expression data
Orthologs
SpeciesHumanMouse
Entrez

1508

13030

Ensembl

ENSG00000164733
ENSG00000285132

ENSMUSG00000021939

UniProt

P07858

P10605

RefSeq (mRNA)

NM_007798

RefSeq (protein)

NP_031824

Location (UCSC)Chr 8: 11.84 – 11.87 MbChr 14: 63.12 – 63.15 Mb
PubMed search[3][4]
Wikidata
View/Edit HumanView/Edit Mouse

Structure

Gene

The CTSB gene is located at chromosome 8p22, consisting of 13 exons. The promoter of CTSB gene contains a GC-rich region including many SP1 sites, which is similar to housekeeping genes.[12] At least five transcript variants encoding the same protein have been found for this gene.[13]

Protein

Cathepsin B is synthesized on the rough endoplasmic reticulum as a preproenzyme of 339 amino acids with a signal peptide of 17 amino acids.[14][15] Procathepsin B of 43/46 kDa is then transported to the Golgi apparatus, where cathepsin B is formed. Mature cathepsin B is composed of a heavy chain of 25-26 kDa and a light chain of 5kDa, which are linked by a dimer of disulfide.

Function

Cathepsin B may enhance the activity of other proteases, including matrix metalloproteinase, urokinase (serine protease urokinase plasminogen activator), and cathepsin D,[16][17] and thus it has an essential position for the proteolysis of extracellular matrix components, intercellular communication disruption, and reduced protease inhibitor expression.[11] It is also involved in autophagy and catabolism, which is advantageous in tumor malignancy, and it is possibly involved in specific immune resistance.[18]

Clinical significance

Cathepsin B has been proposed as a potentially effective biomarker for a variety of cancers.[16][19][20][21][22][23] Overexpression of cathepsin B is correlated with invasive and metastatic cancers.[24] Cathepsin B is produced in muscle tissue during metabolism.[25] It is capable of crossing the blood-brain barrier[26] and is associated with neurogenesis, specifically in the mouse dentate gyrus. A wide array of diseases result in elevated levels of cathepsin B, which causes numerous pathological processes including cell death, inflammation, and production of toxic peptides. Focusing on neurological diseases, cathepsin B gene knockout studies in an epileptic rodent model have shown cathepsin B causes a significant amount of the apoptotic cell death that occurs as a result of inducing epilepsy.[27] Cathepsin B inhibitor treatment of rats in which a seizure was induced resulted in improved neurological scores, learning ability and much reduced neuronal cell death and pro-apoptotic cell death peptides.[28] Similarly, cathepsin B gene knockout and cathepsin B inhibitor treatment studies in traumatic brain injury mouse models have shown that cathepsin B to be key to causing the resulting neuromuscular dysfunction, memory loss, neuronal cell death and increased production of pro-necrotic and pro-apoptotic cell death peptides.[29][30] In ischemic non-human primate and rodent models, cathepsin B inhibitor treatment prevented a significant loss of brain neurons, especially in the hippocampus.[31][32][33] In a Streptococcus pneumoniae meningitis rodent model, cathepsin B inhibitor treatment greatly improved the clinical course of the infection and reduced brain inflammation and inflammatory Interleukin-1β (IL1-β) and tumor necrosis factor-α (TNF-α).[34] In a transgenic Alzheimer's disease (AD) animal model expressing human amyloid precursor protein (APP) containing the wild-type beta-secretase site sequence found in most AD patients or in guinea pigs, which are a natural model of human wild-type APP processing, genetically deleting the cathepsin B gene or chemically inhibiting cathepsin B brain activity resulted in a significant improvement in the memory deficits that develop in such mice and reduces levels of neurotoxic full-length Abeta(1-40/42) and the particularly pernicious pyroglutamate Abeta(3-40/42), which are thought to cause the disease.[35][36][37][38][39][40][41] In a non-transgenic senescence-accelerated mouse strain, which also has APP containing the wild-type beta-secretase site sequence, treatment with bilobalide, which is an extract of Gingko biloba leaves, also lowered brain Abeta by inhibiting cathepsin B.[42] Moreover, siRNA silencing or chemically inhibiting cathepsin B in primary rodent hippocampal cells or bovine chromaffin cells, which have human wild-type beta-secretase activity, reduces secretion of Abeta by the regulated secretory pathway.[43][44] Mutations in the CTSB gene have been linked to tropical pancreatitis, a form of chronic pancreatitis.[45]

Interactions

Cathepsin B has been shown to interact with:

Cathepsin B is inhibited by:

See also

References
  1. ENSG00000285132 GRCh38: Ensembl release 89: ENSG00000164733, ENSG00000285132 - Ensembl, May 2017
  2. GRCm38: Ensembl release 89: ENSMUSG00000021939 - Ensembl, May 2017
  3. "Human PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
  4. "Mouse PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
  5. Sloane BF (April 1990). "Cathepsin B and cystatins: evidence for a role in cancer progression". Seminars in Cancer Biology. 1 (2): 137–52. PMID 2103490.
  6. Chan SJ, San Segundo B, McCormick MB, Steiner DF (October 1986). "Nucleotide and predicted amino acid sequences of cloned human and mouse preprocathepsin B cDNAs". Proceedings of the National Academy of Sciences of the United States of America. 83 (20): 7721–5. doi:10.1073/pnas.83.20.7721. PMC 386793. PMID 3463996.
  7. Cao L, Taggart RT, Berquin IM, Moin K, Fong D, Sloane BF (February 1994). "Human gastric adenocarcinoma cathepsin B: isolation and sequencing of full-length cDNAs and polymorphisms of the gene". Gene. 139 (2): 163–9. doi:10.1016/0378-1119(94)90750-1. PMID 8112600.
  8. Tong B, Wan B, Wei Z, Wang T, Zhao P, Dou Y, Lv Z, Xia Y, Dai Y (September 2014). "Role of cathepsin B in regulating migration and invasion of fibroblast-like synoviocytes into inflamed tissue from patients with rheumatoid arthritis". Clinical and Experimental Immunology. 177 (3): 586–97. doi:10.1111/cei.12357. PMC 4137842. PMID 24749816.
  9. Lai WF, Chang CH, Tang Y, Bronson R, Tung CH (March 2004). "Early diagnosis of osteoarthritis using cathepsin B sensitive near-infrared fluorescent probes". Osteoarthritis and Cartilage. 12 (3): 239–44. doi:10.1016/j.joca.2003.11.005. PMID 14972341.
  10. Ha SD, Ham B, Mogridge J, Saftig P, Lin S, Kim SO (January 2010). "Cathepsin B-mediated autophagy flux facilitates the anthrax toxin receptor 2-mediated delivery of anthrax lethal factor into the cytoplasm". The Journal of Biological Chemistry. 285 (3): 2120–9. doi:10.1074/jbc.M109.065813. PMC 2804368. PMID 19858192.
  11. Yang WE, Ho CC, Yang SF, Lin SH, Yeh KT, Lin CW, Chen MK (2016). "Cathepsin B Expression and the Correlation with Clinical Aspects of Oral Squamous Cell Carcinoma". PLOS ONE. 11 (3): e0152165. doi:10.1371/journal.pone.0152165. PMC 4816521. PMID 27031837.
  12. Qian F, Frankfater A, Chan SJ, Steiner DF (April 1991). "The structure of the mouse cathepsin B gene and its putative promoter". DNA and Cell Biology. 10 (3): 159–68. doi:10.1089/dna.1991.10.159. PMID 2012677.
  13. "Entrez Gene: CTSB cathepsin B".
  14. Kirschke H, Barrett AJ, Rawlings ND (1995). "Proteinases 1: lysosomal cysteine proteinases". Protein Profile. 2 (14): 1581–643. PMID 8771190.
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  17. Vigneswaran N, Zhao W, Dassanayake A, Muller S, Miller DM, Zacharias W (August 2000). "Variable expression of cathepsin B and D correlates with highly invasive and metastatic phenotype of oral cancer". Human Pathology. 31 (8): 931–7. doi:10.1053/hupa.2000.9035. PMID 10987253.
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  28. Ni H, Ren SY, Zhang LL, Sun Q, Tian T, Feng X (February 2013). "Expression profiles of hippocampal regenerative sprouting-related genes and their regulation by E-64d in a developmental rat model of penicillin-induced recurrent epilepticus". Toxicology Letters. 217 (2): 162–9. doi:10.1016/j.toxlet.2012.12.010. PMID 23266720.
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Further reading
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