CTSZ

CTSZ Background

The CTSZ gene mapped to chromosome 20q13 codes for a unique lysosomal cysteine cathepsin Z ^[1], which is expressed primarily by antigen-presenting cells. CTSZ is the only enzyme with strict carboxypeptidase activity ^[2]. Like other cathepsins, CTSZ is produced as a pre-pro-cathepsin Z and then processed to pro-cathepsin Z containing an RGD motif. The RGD motif is located in a highly exposed region of the propeptide, which may allow binding of the proenzyme to RGD-recognizing integrins ^[3], and thus modulating the attachment of migrating cells to ECM components. In the context of neoplasia, there is recent in vivo evidence for a tumor-promoting role for the carboxypeptidase as well as for the RGD function of CTSZ ^[4]. CTSZ can upregulate the proteins associated with extracellular matrix (ECM) remodeling such as MMP2, MMP3, and MMP9, thus indicating that CTSZ might play an important role in hepatocellular carcinoma invasion and metastasis ^[5]. CTSZ is disproportionately expressed and secreted by both microglia and astrocytes in response to neuronal damage and inflammatory stimulus, both in culture and in vivo ^[6][7]. It was reported that dendritic cells in the aging brains of mice had increased expression of CTSZ that associated with known markers of neuroinflammation ^[8]. Euan R. O. Allan et al. demonstrated that CTSZ promotes the IL-1β-Th17 axis leading to more severe neuroinflammation during experimental autoimmune encephalomyelitis (EAE) and may support a new role for CTSZ in the propagation of IL-1β-driven neuroinflammation ^[9]. And it may suggest that CTSZ plays a role in the development of multiple sclerosis (MS), as proposed by Huynh et al. ^[10] .

[1] Santamaría I, Velasco G, et al. Cathepsin Z, a novel human cysteine proteinase with a short propeptide domain and a u5nique chromosomal location [J]. J Biol Chem. 1998 Jul 3; 273(27):16816-23.
[2] Nägler DK, Zhang R, et al. Human cathepsin X: A cysteine protease with unique carboxypeptidase activity [J]. Biochemistry. 1999 Sep 28; 38(39):12648-54.
[3] Lechner AM, Assfalg-Machleidt I, et al. RGD-dependent binding of procathepsin X to integrin αvβ3 mediates cell-adhesive properties [J]. J Biol Chem. 2006;281:39588–97.
[4] Akkari L, Gocheva V, et al. Distinct functions of macrophage-derived and cancer cell-derived cathepsin Z combine to promote tumor malignancy via interactions with the extracellular matrix [J]. Genes Dev. 2014 Oct 1; 28(19):2134-50.
[5] Wang J, Chen L, et al. Overexpression of cathepsin Z contributes to tumor metastasis by inducing epithelial-mesenchymal transition in hepatocellular carcinoma [J]. PLoS One. 2011; 6(9):e24967.
[6] Greco TM, Seeholzer SH, et al. Quantitative mass spectrometry-based proteomics reveals the dynamic range of primary mouse astrocyte protein secretion [J]. J Proteome Res. 2010;9:2764–74.
[7] Wendt W, Schulten R, et al. Intra‐versus extracellular effects of microglia‐derived cysteine proteases in a conditioned medium transfer model [J]. J Neurochem. 2009;110:1931–41.
[8] Stichel CC, Luebbert H. Inflammatory processes in the aging mouse brain: participation of dendritic cells and T-cells [J]. Neurobiol Aging. 2007;28:1507–21.
[9] Euan R. O. Allan, Rhiannon I. Campden, et al. A role for cathepsin Z in neuroinflammation provides mechanistic support for an epigenetic risk factor in multiple sclerosis [J]. J Neuroinflammation. 2017; 14: 103.
[10] Huynh JL, Garg P, et al. Epigenome-wide differences in pathology-free regions of multiple sclerosis-affected brains [J]. Nat Neurosci. 2014 Jan; 17(1):121-30.