CTSB

CTSB Background

Cathepsin B (CTSB) is a lysosomal cysteine protease of the papain family ^[1] and is synthesized on the rough endoplasmic reticulum as a 339-amino acid preproenzyme ^[2]. Pro-cathepsin B is transported to the Golgi apparatus and then is processed into cathepsin B. CTSB has both endopeptidase and exopeptidase activity ^[3]. As an endopeptidase, CTSB is responsible for the cleavage of the S2-P2 specificity protein/peptide substrate ^[4]. While CTSB can cleave two amino acids (dipeptide) from the C-terminal of a polypeptide substrate as an exopeptidase ^[5]. Under normal physiologic conditions, active CTSB is localized in lysosomal and mainly takes part in the routine turnover of both intracellular and extracellular proteins, thus maintaining metabolic homeostatisis ^[6]. CTSB also mediates the regulation of pro-hormone ＆ pro-enzyme activation, antigen processing, inflammatory responses against antigens, tissue remodeling, and apoptosis ^[1][7][8]. In response to certain signals, CTSB and other cathepsins are released from the lysosomes into the cytoplasm where they trigger apoptosis through the promotion of the activation of caspases or the release of proapoptotic factors from the mitochondria ^[9][10]. CTSB can also cleave Bid to produce the active truncated Bid (tBid) ^[11], just like the proteolysis of Bid by caspase 8 early during apoptosis. And CTSB also degrades the anti-apoptotic protein Bcl-xl. Besides, overexpression CTSB is associated with invasive and metastatic cancers ^[12]. The upregulation of CTSB expression can predict poor prognosis in several tumors such as ovarian carcinoma ^[13] and colon carcinoma ^[14].

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[2] Kirschke H, Barrett AJ, Rawlings ND Proteinases 1: lysosomal cysteine proteinases [J]. Protein Profile. 1995; 2(14):1581-643.
[3] Musil D, Zucic D, et al. The refined 2.15 A X-ray crystal structure of human liver cathepsin B: the structural basis for its specificity [J]. EMBO J. 1991 Sep; 10(9):2321-30.
[4] Hasnain S, Hirama T, et al. Characterization of cathepsin B specificity by site-directed mutagenesis. Importance of Glu245 in the S2-P2 specificity for arginine and its role in transition state stabilization [J]. J Biol Chem. 1993 Jan 5; 268(1):235-40.
[5] Cotrin SS, Puzer L, et al. Positional-scanning combinatorial libraries of fluorescence resonance energy transfer peptides to define substrate specificity of carboxydipeptidases: assays with human cathepsin B [J]. Anal Biochem. 2004 Dec 15; 335(2):244-52.
[6] Dora Cavallo-Medved,1 Kamiar Moin, et al. Cathepsin B. Basis Sequence: Mouse [J]. AFCS Nat Mol Pages. 2011; 2011: A000508.
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[8] Linke M, Jordans S, et al. Thyroid-stimulating hormone upregulates secretion of cathepsin B from thyroid epithelial cells [J]. Biol Chem. 2002 May; 383(5):773-84.
[9] Chwieralski CE, Welte T, et al. Cathepsin-regulated apoptosis [J]. Apoptosis 2006; 11: 143-149.
[10] Guicciardi ME, Deussing J, et al. Cathepsin B contributes to TNF-α-mediated hepatocyte apoptosis by promoting mitochondrial release of cytochrome c [J]. J Clin Invest 2000; 106: 1127-11378.
[11] Cirman T, Oresić K, et al. Selective disruption of lysosomes in HeLa cells triggers apoptosis mediated by cleavage of Bid by multiple papain-like lysosomal cathepsins [J]. J Biol Chem 2004; 279: 3578-3587.
[12] Roshy S, Sloane BF, Moin K Pericellular cathepsin B, and malignant progression [J]. Cancer Metastasis Rev. 2003 Jun-Sep; 22(2-3):271-86.
[13] Scorilas A, Fotiou S, et al. Determination of cathepsin B expression may offer additional prognostic information for ovarian cancer patients [J]. Biol Chem. 2002 Jul-Aug; 383(7-8):1297-303
[14] Campo E, Muñoz J, et al. Cathepsin B expression in colorectal carcinomas correlates with tumor progression and shortened patient survival [J]. Am J Pathol. 1994 Aug; 145(2):301-9.