Cathepsin Bbelongs to a family of lysosomalcysteine proteases and plays an important role in intracellular proteolysis. In humans, cathepsin B is encoded by the CTSBgene. Cathepsin B is upregulated in certain cancers, in pre-malignant lesions, and in various other pathological conditions.
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. At least five transcript variants encoding the same protein have been found for this gene.
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. 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.
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 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. 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 and tumor necrosis factor-α. In a transgenic Alzheimer's disease animal model expressing human amyloid precursor protein 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 and the particularly pernicious pyroglutamate Abeta, 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 Gingko 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.
