CTSC

CTSC Background

Cathepsin C (CTSC), also known as Dipeptidyl peptidase I (DPPI), is a cysteine protease of the papain family ^[1] and possesses dipeptidyl aminopeptidase activity that is required for the activation of various granule-associated serine proteases such as neutrophil elastase, cathepsin G, proteinase 3, and granzymes A/B ^[2]. The cysteine cathepsins are monomeric proteins with the sole exception of the tetrameric cathepsin C. CTSC is ubiquitously expressed in many tissues of mammals and other animals. Like other cathepsins, CTSC is synthesized as inactive proenzymes and processed to become mature and active enzymes. Different from related proteases that act as monomeric endopeptidases, CTSC is an oligomeric exopeptidase that generally favors acidic N-terminal sequences until it encounters a stop sequence, usually a charged residue such as lysine, proline, or arginine ^[3]. As an exopeptidase, CTSC can hydrolyze dipeptide esters, amides, anilides, and beta-naphtylamides ^[4]. CTSC also shows transpeptidase activity ^[5]. Koike M et al. demonstrated that CTSC is involved in normal neuronal function in certain brain regions, and also participates in inflammatory processes accompanying pathogenesis in the central nervous system (CNS) ^{[6]. Although CTSC can process many proteases, it is disabled to autoactivate and requires other proteases, presumably endopeptidases such as cathepsin L or cathepsin S, for its activation [7]. Vivien R. Sutton et al. identified that CTSC is responsible for virtually all of the granzymes A (GrA) and most of the granzymes B (GrB) activity in cytotoxic T lymphocytes (CTLs) [8]. In other words, CTSC is critical for activating GrA, while it is not essential for GrB activity. The granzymes are expressed in cytotoxic lymphocytes, where they cooperatively cause the death of transformed and virus-infected cells after their co-secretion with perforin [8]. Perforin allows the access of granzymes and other granule-bound toxins to their substrates within the target cells. As a result, CTSC-null mice retain substantial CTL cytotoxicity, inducing apoptosis in vivo, and in vitro [8][9]. Mutations in the CTSC gene lead to the Papillon-Lefevre syndrome (PLS) [10], a rare autosomal recessive condition that is characterized by symmetrical palmoplantar hyperkeratosis and periodontal inflammation, and loss of both the deciduous and permanent teeth.}

[1] Rao NV, Rao GV, et al. Human dipeptidyl-peptidase I. Gene characterization, localization, and expression [J]. Biol Chem. 1997 Apr 11; 272(15):10260-5.
[2] Radzey H, Rethmeier M, et al. E-64c-hydrazide: a lead structure for the development of irreversible cathepsin C inhibitors [J]. ChemMedChem. 2013 Aug; 8(8):1314-21.
[3] Tran TV, Ellis KA, et al. Dipeptidyl peptidase I: importance of progranzyme activation sequences, other dipeptide sequences, and the N-terminal amino group of synthetic substrates for enzyme activity [J]. Arch Biochem Biophys. 2002 Jul 15; 403(2):160-70.
[4] Minarowska A, Minarowski Ł, et al. Role of cathepsin A and cathepsin C in the regulation of glycosidase activity [J]. Folia Histochem Cytobiol. 2012 Apr 24; 50(1):20-4.
[5] Pagano MB, Bartoli MA, et al. Critical role of dipeptidyl peptidase I in neutrophil recruitment during the development of experimental abdominal aortic aneurysms [J]. Proc Natl Acad Sci U S A. 2007 Feb 20; 104(8):2855-60.
[6] Koike M, Shibata M, et al. Differences in expression patterns of cathepsin C/dipeptidyl peptidase I in normal, pathological and aged mouse central nervous system [J]. Eur J Neurosci. 2013 Mar; 37(5):816-30.
[7] Dahl SW, Halkier T, et al. Human recombinant pro-dipeptidyl peptidase I (cathepsin C) can be activated by cathepsins L and S but not by autocatalytic processing [J]. Biochemistry. 2001 Feb 13; 40(6):1671-8.
[8] Vivien R. Sutton, Nigel J. Waterhouse, et al. Residual active granzyme B in cathepsin C–null lymphocytes is sufficient for perforin-dependent target cell apoptosis [J]. J Cell Biol. 2007 Feb 12; 176(4): 425–433.
[9] Trapani JA, Smyth MJ Functional significance of the perforin/granzyme cell death pathway [J]. Nat Rev Immunol. 2002 Oct; 2(10):735-47.
[10] Farkas K, Paschali E, et al. A novel seven-base deletion of the CTSC gene identified in a Hungarian family with Papillon-Lefèvre syndrome [J]. Arch Dermatol Res. 2013 Jul; 305(5):453-5.