Cathepsin B

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Cathepsin B
PDB 1csb EBI.jpg
Rendering of 1CSB
Available structures
PDB Ortholog search: PDBe, RCSB
External IDs OMIM116810 MGI88561 HomoloGene37550 ChEMBL: 4072 GeneCards: CTSB Gene
EC number
RNA expression pattern
PBB GE CTSB 200839 s at tn.png
PBB GE CTSB 200838 at tn.png
PBB GE CTSB 213274 s at tn.png
More reference expression data
Species Human Mouse
Entrez 1508 13030
Ensembl ENSG00000164733 ENSMUSG00000021939
UniProt P07858 P10605
RefSeq (mRNA) NM_001908 NM_007798
RefSeq (protein) NP_001899 NP_031824
Location (UCSC) Chr 8:
11.7 – 11.73 Mb
Chr 14:
63.12 – 63.15 Mb
PubMed search [1] [2]

Cathepsin B is an enzymatic protein belonging to the peptidase (or protease) families. In humans, it is coded by the CTSB gene.[1][2]


The protein encoded by this gene is a lysosomal cysteine protease composed of a dimer of disulfide-linked heavy and light chains, both produced from a single protein precursor. It is a member of the peptidase C1 family. At least five transcript variants encoding the same protein have been found for this gene.[3]

Clinical significance[edit]

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.[4] 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. [5] 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. [6][7] In ischemic non-human primate and rodent models, cathepsin B inhibitor treatment prevented a significant loss of brain neurons, especially in the hippocampus. [8][9][10] 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-1beta (IL1-beta) and tumor necrosis factor-alpha (TNFalpha).[11] 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. [12][13][14][15][16][17][18] 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. [19] 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. [20][21]

Mutations in the CTSB gene have been linked to tropical pancreatitis, a form of chronic pancreatitis.[22]


Cathepsin B has been shown to interact with cystatin B,[23][24] S100A10[25] and cystatin A.[23][26]

See also[edit]


  1. ^ Chan SJ, San Segundo B, McCormick MB, Steiner DF; San Segundo; McCormick; Steiner (October 1986). "Nucleotide and predicted amino acid sequences of cloned human and mouse preprocathepsin B cDNAs". Proc. Natl. Acad. Sci. U.S.A. 83 (20): 7721–5. doi:10.1073/pnas.83.20.7721. PMC 386793. PMID 3463996. 
  2. ^ Cao L, Taggart RT, Berquin IM, Moin K, Fong D, Sloane BF; Taggart; Berquin; Moin; Fong; Sloane (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. 
  3. ^ "Entrez Gene: CTSB cathepsin B". 
  4. ^ Housewert, M.; Pennacchio, L.A.; Vilaythong, A.; Peters, C.; Noebels, J.L.; Myers, R.M. (2003). "Cathepsin B but not cathepsins L or S contributes to the pathogenesis of Unverricht-Lundborg progressive myoclonus epilepsy (EPM1)". J Neurobiol 56: 315–27. 
  5. ^ Ni, H.; Ren, S.Y.; Zhang, L.L.; Sun, Q.; Tian, T.; Feng, X. (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". Toxicol Lett 217 (2): 162–9 Extra |pages= or |at= (help). doi:10.1016/j.toxlet.2012.12.010. PMID 23266720. 
  6. ^ Hook, G.; Yu, J.; Sipes, N.; Pierschbacher, M.; Hook, V.; Kindy, M.S. (2013). "The Cysteine Protease Cathepsin B is a Key Drug Target and Cysteine Protease Inhibitors are Potential Therapeutics for Traumatic Brain Injury". J Neurotrauma 31 (5): 515–529 Extra |pages= or |at= (help). doi:10.1089/neu.2013.2944. PMC 3934599. PMID 24083575. 
  7. ^ Luo, C.L.; Chen, X.P.; Yang, R.; Sun, Y.X.; Li, Q.Q.; Bao, H.J.; Cao, Q.Q.; Ni, H.; Qin, Z.H.; Tao, L.Y. (2010). "Cathepsin B contributes to traumatic brain injury-induced cell death through a mitochondria-mediated apoptotic pathway". J Neurosci Res 88 (13): 2847–58. PMID 20653046. 
  8. ^ Yoshida, M.; Yamashima, T.; Zhao, L.; Tsuchiya, K.; Kohda, Y.; Tonchev, A.B.; Matsuda, M.; Kominami, E. (2002). "Primate neurons show different vulnerability to transient ischemia and response to cathepsin inhibition". Acta Neuropathol (Berl) 104 (3): 267–72. PMID 12172912. 
  9. ^ Tsuchiya, K.; Kohda, Y.; Yoshida, M.; Zhao, L.; Ueno, T.; Yamashita, J.; Yoshioka, J.; Kominami, E.; Yamashima, T. (1999). "Postictal blockade of ischemic hippocampal neuronal death in primates using selective cathepsin inhibitors". Exp Neurol 155 (2): 187–94. doi:10.1006/exnr.1998.6988. PMID 10072294. 
  10. ^ Tsubokawa, T.; Yamaguchi-Okada, M.; Calvert, J.W.; Solaroglu, I.; Shimamura, N.; Yata, K.; Zhang, J.H. (2006). "Neurovascular and neuronal protection by E64d after focal cerebral ischemia in rats". J Neurosci Res 84 (4): 832–40. doi:10.1002/jnr.20977. PMID 16802320. 
  11. ^ Hoegen, T.; Tremel, N.; Klein, M.; Angele, B.; Wagner, H.; Kirschning, C.; Pfister, H.W.; Fontana, A.; Hammerschmidt, S.; Koedel, U. (2011). "The NLRP3 inflammasome contributes to brain injury in pneumococcal meningitis and is activated through ATP-dependent lysosomal cathepsin B release". J Immunol 187 (10): 5440–51. doi:10.4049/jimmunol.1100790. PMID 22003197. 
  12. ^ Hook, V.Y.; Kindy, M.; Hook, G. (2008). "Inhibitors of cathepsin B improve memory and reduce Abeta in transgenic Alzheimer's Disease mice expressing the wild-type, but not the Swedish mutant, beta -secretase APP site". J Biol Chem 283 (12): 7745–7753. doi:10.1074/jbc.m708362200. PMID 18184658. 
  13. ^ Hook, V.; Kindy, M.; Hook, G. (2007). "Cysteine protease inhibitors effectively reduce in vivo levels of brain beta-amyloid related to Alzheimer's disease". Biol Chem 388 (2): 247–52. doi:10.1515/bc.2007.027. PMID 17261088. 
  14. ^ Hook, G.; Hook, V.Y.; Kindy, M. (2007). "Cysteine protease inhibitors reduce brain beta-amyloid and beta-secretase activity in vivo and are potential Alzheimer's disease therapeutics". Biol Chem 388 (9): 979–83. doi:10.1515/BC.2007.117. PMID 17696783. 
  15. ^ Hook, V.Y.; Kindy, M.; Reinheckel, T.; Peters, C.; Hook, G. (2009). "Genetic cathepsin B deficiency reduces beta-amyloid in transgenic mice expressing human wild-type amyloid precursor protein". Biochem Biophys Res Commun 386 (2): 284–8. doi:10.1016/j.bbrc.2009.05.131. PMID 19501042. 
  16. ^ Hook, G.; Hook, V.; Kindy, M. (2011). "The Cysteine Protease Inhibitor, E64d, Reduces Brain Amyloid-beta and Improves Memory Deficits in Alzheimer's Disease Animal Models by Inhibiting Cathepsin B, but not BACE1, beta-Secretase Activity". J Alzheimers Dis 26 (2): 387–408. PMID 21613740. 
  17. ^ Kindy, M.S.; Yu, J.; Zhu, H.; El-Amouri, S.S.; Hook, V.; Hook, G.R. (2012). "Deletion of the Cathepsin B Gene Improves Memory Deficits in a Transgenic Alzheimer's Disease Mouse Model Expressing AbetaPP Containing the Wild-Type beta-Secretase Site Sequence". J Alzheimers Dis 29 (4): 827–40. PMID 22337825. 
  18. ^ Hook, G.; Yu, J.; Toneff, T.; Kindy, M.; Hook, V. (2014). "Brain pyroglutamate amyloid-beta is produced by cathepsin B and is reduced by the cysteine protease inhibitor E64d, representing a potential Alzheimer's disease therapeutic". J Alzheimers Dis 41 (1): 129–49. PMID 24595198. 
  19. ^ Shi, C.; Zheng, D.D.; Wu, F.M.; Liu, J.; Xu, J. (2012). "The phosphatidyl inositol 3 kinase-glycogen synthase kinase 3beta pathway mediates bilobalide-induced reduction in amyloid beta-peptide". Neurochem Res 37 (2): 298–306. doi:10.1007/s11064-011-0612-1. PMID 21952928. 
  20. ^ Hook, V.; Tonneff, T.; Bogyo, M.; Medzihradszky, K.F.; Nevenu, J.; Lane, W.; Hook, G.; Reisine, T.; Reisine, T (2005). "Inhibition of cathepsin B reduces β-amyloid production in regulated secretory vesicles of neuronal chromaffin cells: evidence for cathepsin B as a candidate β-secretase of Alzheimer's disease". Biological Chemistry 386 (9): 931–940. doi:10.1515/BC.2005.108. PMID 16164418. 
  21. ^ Klein, D.M.; Felsentein, K.M.; Brenneman, D.E. (2009). "Cathepsins B and L differentially regulate amyloid precursor protein processing". J Pharmacol Exp Ther 329 (3): 813–21. PMID 19064719. 
  22. ^ Tandon RK (January 2007). "Tropical pancreatitis". J. Gastroenterol. 42 (Suppl 17): 141–7. doi:10.1007/s00535-006-1930-y. PMID 17238044. 
  23. ^ a b Pavlova A, Björk I; Björk (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. PMID 14503883. 
  24. ^ Pol E, Björk I; Björk (September 2001). "Role of the single cysteine residue, Cys 3, of human and bovine cystatin B (stefin B) in the inhibition of cysteine proteinases". Protein Sci. 10 (9): 1729–38. doi:10.1110/ps.11901. PMC 2253190. PMID 11514663. 
  25. ^ Mai J, Finley RL, Waisman DM, Sloane BF; Finley Jr; Waisman; Sloane (April 2000). "Human procathepsin B interacts with the annexin II tetramer on the surface of tumor cells". J. Biol. Chem. 275 (17): 12806–12. doi:10.1074/jbc.275.17.12806. PMID 10777578. 
  26. ^ Estrada S, Nycander M, Hill NJ, Craven CJ, Waltho JP, Björk I; Nycander; Hill; Craven; Waltho; Björk (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. PMID 9585570. 

Further reading[edit]

  • Yan S, Sloane BF; Sloane (2004). "Molecular regulation of human cathepsin B: implication in pathologies". Biol. Chem. 384 (6): 845–54. doi:10.1515/BC.2003.095. PMID 12887051. 

External links[edit]