Cathepsin B is in humans encoded by the CTSBgene. Cathepsin B belongs to a family of lysosomalcysteineproteases and plays an important role in intracellular proteolysis. Upregulation of cathepsin B is found in premalignant lesions and various pathological conditions, as well as cancers.
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 gene. At least five transcript variants encoding the same protein have been found for this gene.
Cathepsin B is synthesized on the rough endoplasmic reticulum as a preproenzyme of 339 amino acid with a signal peptide of 17 amino acids. Procathepsin B of 43/46 kDa is then transported to the Golgi apparatus and 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.
Cathepsin B may enhance the activity of other protease, including matrix metalloproteinase, urokinase (serine protease urokinase plasminogen activator), and cathepsin D, and thus it has an essential position for in the proteolysis of extracellular matrix components, intercellular communication disruption, and reduced protease inhibitor expression. It is also involved in autophagy and catabolism, which is advantageous in tumor malignancy and is possibly involved in specific immune resistance.
Cathepsin B has been proposed as a potentially effective biomarker for a variety of cancers. Overexpression of cathepsin B is correlated with invasive and metastatic cancers.
Cathepsin B is produced in muscle tissue during metabolism. It is capable of crossing the blood-brain barrier 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. 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. Similarly, cathepsin B gene knockout and cathepsin B inhibitor treatment studies in traumatic brain injury mouse models have shown 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. In ischemic non-human primate and rodent models, cathepsin B inhibitor treatment prevented a significant loss of brain neurons, especially in the hippocampus. In a streptococcus pneumoniaemeningitis 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). 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. 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 Ginko biloba leaves, also lowered brain Abeta by inhibiting cathepsin B. 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.Mutations in the CTSB gene have been linked to tropical pancreatitis, a form of chronic pancreatitis.
^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. PMID2012677.
^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. PMID10987253.
^Bao W, Fan Q, Luo X, Cheng WW, Wang YD, Li ZN, Chen XL, Wu D (August 2013). "Silencing of Cathepsin B suppresses the proliferation and invasion of endometrial cancer". Oncology Reports. 30 (2): 723–30. doi:10.3892/or.2013.2496. PMID23708264.
^Yin M, Soikkeli J, Jahkola T, Virolainen S, Saksela O, Hölttä E (December 2012). "TGF-β signaling, activated stromal fibroblasts, and cysteine cathepsins B and L drive the invasive growth of human melanoma cells". The American Journal of Pathology. 181 (6): 2202–16. doi:10.1016/j.ajpath.2012.08.027. PMID23063511.
^Moon HY, Becke A, Berron D, Becker B, Sah N, Benoni G, Janke E, Lubejko ST, Greig NH, Mattison JA, Duzel E, van Praag H (June 2016). "Running-Induced Systemic Cathepsin B Secretion Is Associated with Memory Function". Cell Metabolism. 24: 332–40. doi:10.1016/j.cmet.2016.05.025. PMID27345423.
^Houseweart MK, Pennacchio LA, Vilaythong A, Peters C, Noebels JL, Myers RM (September 2003). "Cathepsin B but not cathepsins L or S contributes to the pathogenesis of Unverricht-Lundborg progressive myoclonus epilepsy (EPM1)". Journal of Neurobiology. 56 (4): 315–27. doi:10.1002/neu.10253. PMID12918016.
^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. PMID23266720.
^Luo CL, Chen XP, Yang R, Sun YX, Li QQ, Bao HJ, Cao QQ, Ni H, Qin ZH, Tao LY (October 2010). "Cathepsin B contributes to traumatic brain injury-induced cell death through a mitochondria-mediated apoptotic pathway". Journal of Neuroscience Research. 88 (13): 2847–58. doi:10.1002/jnr.22453. PMID20653046.
^Yoshida M, Yamashima T, Zhao L, Tsuchiya K, Kohda Y, Tonchev AB, Matsuda M, Kominami E (September 2002). "Primate neurons show different vulnerability to transient ischemia and response to cathepsin inhibition". Acta Neuropathologica. 104 (3): 267–72. doi:10.1007/s00401-002-0554-4. PMID12172912.
^Tsuchiya K, Kohda Y, Yoshida M, Zhao L, Ueno T, Yamashita J, Yoshioka T, Kominami E, Yamashima T (February 1999). "Postictal blockade of ischemic hippocampal neuronal death in primates using selective cathepsin inhibitors". Experimental Neurology. 155 (2): 187–94. doi:10.1006/exnr.1998.6988. PMID10072294.
^Tsubokawa T, Yamaguchi-Okada M, Calvert JW, Solaroglu I, Shimamura N, Yata K, Zhang JH (September 2006). "Neurovascular and neuronal protection by E64d after focal cerebral ischemia in rats". Journal of Neuroscience Research. 84 (4): 832–40. doi:10.1002/jnr.20977. PMID16802320.
^Hoegen T, Tremel N, Klein M, Angele B, Wagner H, Kirschning C, Pfister HW, Fontana A, Hammerschmidt S, Koedel U (November 2011). "The NLRP3 inflammasome contributes to brain injury in pneumococcal meningitis and is activated through ATP-dependent lysosomal cathepsin B release". Journal of Immunology. 187 (10): 5440–51. doi:10.4049/jimmunol.1100790. PMID22003197.
^Hook VY, Kindy M, Hook G (March 2008). "Inhibitors of cathepsin B improve memory and reduce beta-amyloid in transgenic Alzheimer disease mice expressing the wild-type, but not the Swedish mutant, beta-secretase site of the amyloid precursor protein". The Journal of Biological Chemistry. 283 (12): 7745–53. doi:10.1074/jbc.m708362200. PMID18184658.
^Hook V, Kindy M, Hook G (February 2007). "Cysteine protease inhibitors effectively reduce in vivo levels of brain beta-amyloid related to Alzheimer's disease". Biological Chemistry. 388 (2): 247–52. doi:10.1515/bc.2007.027. PMID17261088.
^Hook G, Hook VY, Kindy M (September 2007). "Cysteine protease inhibitors reduce brain beta-amyloid and beta-secretase activity in vivo and are potential Alzheimer's disease therapeutics". Biological Chemistry. 388 (9): 979–83. doi:10.1515/BC.2007.117. PMID17696783.
^Hook V, Toneff T, Bogyo M, Greenbaum D, Medzihradszky KF, Neveu J, Lane W, Hook G, Reisine T (September 2005). "Inhibition of cathepsin B reduces beta-amyloid production in regulated secretory vesicles of neuronal chromaffin cells: evidence for cathepsin B as a candidate beta-secretase of Alzheimer's disease". Biological Chemistry. 386 (9): 931–40. doi:10.1515/BC.2005.108. PMID16164418.
^Klein DM, Felsenstein KM, Brenneman DE (March 2009). "Cathepsins B and L differentially regulate amyloid precursor protein processing". The Journal of Pharmacology and Experimental Therapeutics. 328 (3): 813–21. doi:10.1124/jpet.108.147082. PMID19064719.
^ abPavlova A, Björk I (September 2003). "Grafting of features of cystatins C or B into the N-terminal region or second binding loop of cystatin A (stefin A) substantially enhances inhibition of cysteine proteinases". Biochemistry. 42 (38): 11326–33. doi:10.1021/bi030119v. PMID14503883.
^Estrada S, Nycander M, Hill NJ, Craven CJ, Waltho JP, Björk I (May 1998). "The role of Gly-4 of human cystatin A (stefin A) in the binding of target proteinases. Characterization by kinetic and equilibrium methods of the interactions of cystatin A Gly-4 mutants with papain, cathepsin B, and cathepsin L". Biochemistry. 37 (20): 7551–60. doi:10.1021/bi980026r. PMID9585570.
^Mai J, Finley RL, Waisman DM, Sloane BF (April 2000). "Human procathepsin B interacts with the annexin II tetramer on the surface of tumor cells". The Journal of Biological Chemistry. 275 (17): 12806–12. doi:10.1074/jbc.275.17.12806. PMID10777578.