Cathepsin B

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Cathepsin B
PDB 1csb EBI.jpg
Rendering of 1CSB
Available structures
PDB Ortholog search: PDBe, RCSB
Identifiers
Symbols CTSB ; APPS; CPSB
External IDs OMIM116810 MGI88561 HomoloGene37550 ChEMBL: 4072 GeneCards: CTSB Gene
EC number 3.4.22.1
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
Orthologs
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 (CatB) is an enzymatic protein belonging to the peptidase (or protease) families. In humans, it is coded by the CTSB gene.[1][2]

Function[edit]

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]

Interactions[edit]

Cathepsin B has been shown to interact with:

See also[edit]


References[edit]

  1. ^ 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". 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 (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. ^ Houseweart MK, Pennacchio LA, Vilaythong A, Peters C, Noebels JL, Myers RM (2003). "Cathepsin B but not cathepsins L or S contributes to the pathogenesis of Unverricht-Lundborg progressive myoclonus epilepsy (EPM1)". J. Neurobiol. 56 (4): 315–27. doi:10.1002/neu.10253. PMID 12918016. 
  5. ^ Ni H, Ren SY, Zhang LL, 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. doi:10.1016/j.toxlet.2012.12.010. PMID 23266720. 
  6. ^ Hook GR, Yu J, Sipes N, Pierschbacher MD, Hook V, Kindy MS (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): 515–29. doi:10.1089/neu.2013.2944. PMC 3934599. PMID 24083575. 
  7. ^ Luo CL, Chen XP, Yang R, Sun YX, Li QQ, Bao HJ et al. (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 AB et al. (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 et al. (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 JW, Solaroglu I, Shimamura N, Yata K et al. (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 et al. (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 VY, 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 VY, 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 VY, 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 MS, Yu J, Zhu H, El-Amouri SS, Hook V, Hook GR (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 DD, Wu FM, 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, Toneff T, Bogyo M, Greenbaum D, Medzihradszky KF, Neveu J et al. (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 DM, Felsenstein KM, Brenneman DE (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 (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.  Vancouver style error (help)
  24. ^ 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. PMID 9585570.  Vancouver style error (help)
  25. ^ Pol E, Björk I (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.  Vancouver style error (help)
  26. ^ 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". J. Biol. Chem. 275 (17): 12806–12. doi:10.1074/jbc.275.17.12806. PMID 10777578. 

Further reading[edit]

  • Yan S, Sloane BF (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]