Alternative titles; symbols
HGNC Approved Gene Symbol: CTSL
Cytogenetic location: 9q21.33 Genomic coordinates (GRCh38): 9:87,726,119-87,731,469 (from NCBI)
Cathepsin L is a lysosomal cysteine proteinase with a major role in intracellular protein catabolism. It also shows the most potent collagenolytic and elastinolytic activity in vitro of any of the cathepsins. Cathepsin L proteolytically inactivates alpha-1 protease inhibitor (107400), a major controlling element of human neutrophil elastase (130130) activity in vivo. Cathepsin L has been implicated in pathologic processes including myofibril necrosis in myopathies and in myocardial ischemia, and in the renal tubular response to proteinuria (Joseph et al., 1988).
Human liver cathepsin L consists of a heavy chain of about 25 kD and a light chain of about 5 kD. Mason et al. (1986) partially sequenced the 2 peptides and determined that they are derived proteolytically from a single polypeptide precursor.
Joseph et al. (1988) presented the complete nucleotide sequence and predicted amino acid sequence for human preprocathepsin L. The deduced 333-amino acid protein begins with a 17-amino acid signal sequence, followed by a 96-amino acid propeptide that is absent from the heavy chain in the mature protein. CATL also contains a single N-glycosylation site. Mouse Catl shares 72% amino acid identity with human CATL, and it contains 2 N-glycosylation sites. Northern blot analysis detected a 1.5-kb transcript in a human breast tumor and in human kidney. A 4.0-kb transcript was also expressed in kidney.
Mouse fibroblasts that are malignantly transformed are stimulated by growth factors or tumor promoters to synthesize and secrete increased amounts of a 39-kD glycoprotein with acid-proteinase activity. This protein, termed MEP for major excreted protein, is a precursor for 2 lysosomal proteins of lower molecular weight and contains the lysosomal recognition marker mannose 6-phosphate. By cross-hybridization with a mouse MEP cDNA clone, Gal and Gottesman (1988) isolated and characterized a full-length human MEP cDNA clone. A 1.6-kb cDNA showed 70% deduced amino acid sequence identity with mouse MEP. The deduced amino acid sequence of the cloned human MEP was the same, except for 2 amino acids, as the N-terminal sequence of mature human cathepsin L, thereby establishing that human MEP is human procathepsin L.
Chauhan et al. (1993) demonstrated concurrent expression of 2 distinct human cathepsin L mRNAs, CATLA and CATLB, in adenocarcinoma, hepatoma, and renal cancer cell lines. CATLA corresponds to the cDNA cloned by Gal and Gottesman (1988) from human fibroblasts, and CATLB corresponds to the cDNA cloned by Joseph et al. (1988) from human kidney. CATLA and CATLB differ only in the 5-prime noncoding region. Expression of CATLB mRNA was consistently several-fold higher than expression of CATLA mRNA in all human cell lines examined. Cloning and subsequent sequencing of genomic DNA demonstrated that the 2 mRNAs are encoded by a single gene. The 3-prime end of the first intron contains the 5-prime portion of CATLB and is contiguous to the second exon of the gene. The data suggested either the possibility of alternative splicing or the presence of a second promoter within the first intron of the CATL gene.
Abudula et al. (2001) cloned 3 CATL variants, CATLA, CATLA2, and CATLA3, that differ only in the length of exon 1. They were unable to clone the CATLB variant. The shortest variant, CATLA3, predominated in all tissues and cells examined. The 5-prime UTRs of the splice variants determined different translation rates in vivo.
Using RT-PCR, Arora and Chauhan (2002) detected expression of the CATLA, CATLA1, CATLA2, and CATLA3 splice variants in several human tumor cell lines, and they cloned these variants from an epidermoid carcinoma cell line. All CATL variants, including CATLB, have an identical open reading frame and differ only in the 5-prime UTR. SDS-PAGE and densitometric analysis of the products of in vitro translation and examination of the promoter activity of each 5-prime UTR indicated that the CATLA variants differ in their translational efficiencies.
Ohashi et al. (2003) purified a 31-kD IL8 (146930)-converting enzyme from the supernatant of cultured human diploid fibroblasts. Sequence analysis indicated that the IL8-converting enzyme is a secreted form of cathepsin L.
By gene expression profiling of endothelial progenitor cells and mature endothelial cells, Urbich et al. (2005) found that cathepsin L is highly expressed in progenitor cells compared to mature endothelial cells and is essential for matrix degradation and invasion in vitro. Ctsl-null mice showed impaired functional recovery following hind limb ischemia, and infused Ctsl-deficient progenitor cells neither homed to sites of ischemia nor augmented neovascularization. Forced expression of cathepsin L in mature endothelial cells enhanced invasive activity and neovascularization in vivo. Urbich et al. (2005) concluded that cathepsin L has a critical role in the integration of circulating endothelial progenitor cells into ischemic tissue and is required for endothelial progenitor cell-mediated neovascularization.
In studies in cultured mouse podocytes and rodent models of proteinuria, Sever et al. (2007) showed that during proteinuric kidney disease, induction of cytoplasmic CTSL led to cleavage of the GTPase dynamin (see DNM2, 602378) at a conserved site, resulting in reorganization of the podocyte actin cytoskeleton and proteinuria. Dynamin mutants that lacked the CTSL site, or rendered the CTSL site inaccessible through dynamin self-assembly, were resistant to CTSL cleavage. When delivered into mice, these mutants restored podocyte function and resolved proteinuria. Sever et al. (2007) concluded that proteolytic processing of dynamin by cytoplasmic CTSL is a mechanism for proteinuric kidney disease.
Using selective protease inhibitors in African green monkey kidney cells and protease-deficient mouse cell lines, Chandran et al. (2005) identified an essential role for Catb (CTSB; 116810) and an accessory role for Catl in the entry of vesicular stomatitis virus particles pseudotyped with Ebola virus glycoprotein. They proposed that CATB and CATL are part of a multistep mechanism contributing to Ebola virus infection and that cathepsin inhibitors that diminish viral multiplication may have a role in antiviral therapy.
Chauhan et al. (1993) determined that the cathepsin L gene contains 8 exons and spans about 5.1 kb. The translation start codon resides in exon 2.
Bakhshi et al. (2001) identified 29 different putative transcription factor binding sites, some present more than once, within the promoter region responsible for transcription of the CATLA variants. They identified a CAAT box but no consensus TATA box within the 1.0-kb region upstream of exon 1.
Seth et al. (2003) identified the promoter region responsible for transcription of the CATLB variant. The CATLB promoter is an alternate TATA-less promoter in the 3-prime region of the first intron of the CATL gene. It has a low GC content and has an AAAT motif repeated 10 times. CATLB synthesis is initiated from 2 different cytosines that are 191 and 367 bp upstream of the translation start codon.
Using the clones prepared by Joseph et al. (1988) for in situ hybridization and Southern analysis of human-mouse cell hybrids, Fan et al. (1989) assigned the CTSL gene to 9q21-q22. Because of hybridizing bands that cosegregated with human chromosome 10, they concluded that there is a similar sequence, perhaps a cathepsin L-like gene (CTSLL), located on chromosome 10.
Chauhan et al. (1993) mapped the gene to 9q21-q22 by radioisotopic in situ hybridization and also located the gene on chromosome 9 by PCR amplification of rodent/human somatic cell hybrid DNAs. By in situ hybridization, they also found a second signal at 10q23-q24 and pointed out that this might be related to the fact that chromosomes 9 and 10 show evolutionary homeology.
By interspecific backcross linkage analysis, Pilz et al. (1995) mapped the Ctsl gene to mouse chromosome 13.
Stypmann et al. (2002) examined the role of intracellular proteolysis in the remodeling that underlies dilated cardiomyopathy and found that CTSL is critical for cardiac morphology and function. One-year-old Ctsl-deficient mice showed significant ventricular and atrial enlargement associated with a comparatively small increase in relative heart weight. Interstitial fibrosis and pleomorphic nuclei were found in the myocardium of the knockout mice. By electron microscopy, Ctsl-deficient cardiomyocytes contained multiple large and apparently fused lysosomes characterized by storage of electron-dense heterogeneous material. In parallel, the assessment of left ventricular function by echocardiography revealed severely impaired myocardial contraction in the Ctsl-deficient mice. In addition, echocardiographic and electrocardiographic findings pointed to left ventricular hypertrophy that most likely represented an adaptive response to cardiac impairment. The histomorphologic and functional alterations of Ctsl-deficient hearts resulted in valve insufficiencies. Furthermore, abnormal heart rhythms, like supraventricular tachycardia, ventricular extrasystoles, and first-degree atrioventricular block, were detected in the Ctsl-deficient mice.
Honey et al. (2002) found that mice lacking Ctsl lack the predominant V-alpha-14+ subset of regulatory natural killer T (NKT) cells, whereas the small subset expressing the TCRA (see 186880) chain V-alpha-3.2+ develop without impairment. Flow cytometric analysis and confocal and immunoelectron microscopy demonstrated that Cd1d (188410) cell surface expression and intracellular localization are normal in Ctsl-deficient thymocytes, as is the structure and number of lysosomes. The authors concluded that Ctsl is a critical regulator of Cd1d presentation of endogenous V-alpha-14+ NKT ligands.
Lysosomal proteases generate peptides presented by class II MHC molecules to CD4+ T cells. To determine whether specific lysosomal proteases influence the outcome of a CD4+ T cell-dependent autoimmune response, Maehr et al. (2005) generated mice that lack Ctsl on the autoimmune diabetes-prone NOD inbred background. The absence of Ctsl afforded strong protection from disease at the stage of pancreatic infiltration. Within the CD4+ T cell compartments of the Ctsl-deficient mice, there was an increased proportion of regulatory T cells compared with that in Ctsl-sufficient littermates. Maehr et al. (2005) suggested that it is this displaced balance of regulatory versus aggressive CD4+ T cells that protects Ctsl-deficient mice from autoimmune disease. The results identified Ctsl as an enzyme whose activity is essential for the development of type I diabetes (222100) in the NOD mouse.
Abudula, A., Rommerskirch, W., Weber, E., Gunther, D., Wiederanders, B. Splice variants of human cathepsin L mRNA show different expression rates. Biol. Chem. 382: 1583-1591, 2001. [PubMed: 11767948] [Full Text: https://doi.org/10.1515/BC.2001.193]
Arora, S., Chauhan, S. S. Identification and characterization of a novel human cathepsin L splice variant. Gene 293: 123-131, 2002. [PubMed: 12137950] [Full Text: https://doi.org/10.1016/s0378-1119(02)00700-x]
Bakhshi, R., Goel, A., Seth, P., Chhikara, P., Chauhan, S. S. Cloning and characterization of human cathepsin L promoter. Gene 275: 93-101, 2001. [PubMed: 11574156] [Full Text: https://doi.org/10.1016/s0378-1119(01)00650-3]
Chandran, K., Sullivan, N. J., Felbor, U., Whelan, S. P., Cunningham, J. M. Endosomal proteolysis of the Ebola virus glycoprotein is necessary for infection. Science 308: 1643-1645, 2005. [PubMed: 15831716] [Full Text: https://doi.org/10.1126/science.1110656]
Chauhan, S. S., Popescu, N. C., Ray, D., Fleischmann, R., Gottesman, M. M., Troen, B. R. Cloning, genomic organization, and chromosomal localization of human cathepsin L. J. Biol. Chem. 268: 1039-1045, 1993. [PubMed: 8419312]
Fan, Y.-S., Byers, M. G., Eddy, R. L., Joseph, L., Sukhatme, V., Chan, S.-J., Shows, T. B. Cathepsin L (CTSL) is located in the chromosome 9q21-q22 region: a related sequence is located on chromosome 10. (Abstract) Cytogenet. Cell Genet. 51: 996 only, 1989.
Gal, S., Gottesman, M. M. Isolation and sequence of a cDNA for human pro-(cathepsin L). Biochem. J. 253: 303-306, 1988. [PubMed: 3421948] [Full Text: https://doi.org/10.1042/bj2530303]
Honey, K., Benlagha, K., Beers, C., Forbush, K., Teyton, L., Kleijmeer, M. J., Rudensky, A. Y., Bendelac, A. Thymocyte expression of cathepsin L is essential for NKT cell development. Nature Immun. 3: 1069-1074, 2002. [PubMed: 12368909] [Full Text: https://doi.org/10.1038/ni844]
Joseph, L. J., Chang, L. C., Stamenkovich, D., Sukhatme, V. P. Complete nucleotide and deduced amino acid sequences of human and murine preprocathepsin L: an abundant transcript induced by transformation of fibroblasts. J. Clin. Invest. 81: 1621-1629, 1988. [PubMed: 2835398] [Full Text: https://doi.org/10.1172/JCI113497]
Maehr, R., Mintern, J. D., Herman, A. E., Lennon-Dumenil, A.-M., Mathis, D., Benoist, C., Ploegh, H. L. Cathepsin L is essential for onset of autoimmune diabetes in NOD mice. J. Clin. Invest. 115: 2934-2943, 2005. [PubMed: 16184198] [Full Text: https://doi.org/10.1172/JCI25485]
Mason, R. W., Walker, J. E., Northrop, F. D. The N-terminal amino acid sequences of the heavy and light chains of human cathepsin L: relationship to a cDNA clone for a major cysteine proteinase from a mouse macrophage cell line. Biochem. J. 240: 373-377, 1986. [PubMed: 3545185] [Full Text: https://doi.org/10.1042/bj2400373]
Ohashi, K., Naruto, M., Nakaki, T., Sano, E. Identification of interleukin-8 converting enzyme as cathepsin L. Biochim. Biophys. Acta 1649: 30-39, 2003. [PubMed: 12818188] [Full Text: https://doi.org/10.1016/s1570-9639(03)00152-3]
Pilz, A., Woodward, K., Povey, S., Abbott, C. Comparative mapping of 50 human chromosome 9 loci in the laboratory mouse. Genomics 25: 139-149, 1995. [PubMed: 7774911] [Full Text: https://doi.org/10.1016/0888-7543(95)80119-7]
Seth, P., Mahajan, V. S., Chauhan, S. S. Transcription of human cathepsin L mRNA species hCATL B from a novel alternative promoter in the first intron of its gene. Gene 321: 83-91, 2003. [PubMed: 14636995] [Full Text: https://doi.org/10.1016/s0378-1119(03)00838-2]
Sever, S., Altintas, M. M., Nankoe, S. R., Moller, C. C., Ko, D., Wei, C., Henderson, J., del Re, E. C., Hsing, L., Erickson, A., Cohen, C. D., Kretzler, M., Kerjaschki, D., Rudensky, A., Nikolic, B., Reiser, J. Proteolytic processing of dynamin by cytoplasmic cathepsin L is a mechanism for proteinuric kidney disease. J. Clin. Invest. 117: 2095-2104, 2007. [PubMed: 17671649] [Full Text: https://doi.org/10.1172/JCI32022]
Stypmann, J., Glaser, K., Roth, W., Tobin, D. J., Petermann, I., Matthias, R., Monnig, G., Haverkamp, W., Breithardt, G., Schmahl, W., Peters, C., Reinheckel, T. Dilated cardiomyopathy in mice deficient for the lysosomal cysteine peptidase cathepsin L. Proc. Nat. Acad. Sci. 99: 6234-6239, 2002. [PubMed: 11972068] [Full Text: https://doi.org/10.1073/pnas.092637699]
Urbich, C., Heeschen, C., Aicher, A., Sasaki, K., Bruhl, T., Farhadi, M. R., Vajkoczy, P., Hofmann, W. K., Peters, C., Pennacchio, L. A., Abolmaali, N. D., Chavakis, E., Reinheckel, T., Zeiher, A. M., Dimmeler, S. Cathepsin L is required for endothelial progenitor cell-induced neovascularization. Nature Med. 11: 206-213, 2005. [PubMed: 15665831] [Full Text: https://doi.org/10.1038/nm1182]