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Cathepsin Z, a Novel Human Cysteine Proteinase with a Short Propeptide Domain and a Unique Chromosomal Location*

  • Iñigo Santamarı́a
    Footnotes
    Affiliations
    Departamento de Bioquı́mica y Biologı́a Molecular, Universidad de Oviedo, 33006-Oviedo, Spain
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  • Gloria Velasco
    Affiliations
    Departamento de Bioquı́mica y Biologı́a Molecular, Universidad de Oviedo, 33006-Oviedo, Spain
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  • Alberto M. Pendás
    Affiliations
    Departamento de Bioquı́mica y Biologı́a Molecular, Universidad de Oviedo, 33006-Oviedo, Spain
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  • Antonio Fueyo
    Affiliations
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  • Carlos López-Otı́n
    Correspondence
    To whom correspondence should be addressed: Departamento de Bioquı́mica y Biologı́a Molecular, Facultad de Medicina, Universidad de Oviedo, 33006 Oviedo, Spain. Tel.: 34-85-104201; Fax: 34-85-103564 or 34-85-232255;
    Affiliations
    Departamento de Bioquı́mica y Biologı́a Molecular, Universidad de Oviedo, 33006-Oviedo, Spain
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  • Author Footnotes
    * This work was supported by Grant SAF97-0258 from the Comisión Interministerial de Ciencia y Tecnologı́a, Grant BMH4-CT96–0017 from EU-BIOMED II, and grants from Glaxo-Wellcome, Spain. The costs of publication of this article were defrayed in part by the payment of page charges. The article must therefore be hereby marked “advertisement” in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.The nucleotide sequence(s) reported in this paper has been submitted to the GenBank™/EMBL Data Bank with accession number(s) AF032906.
    ‡ Recipient of a fellowship from Ministerio de Educación y Ciencia (Spain).
Open AccessPublished:July 03, 1998DOI:https://doi.org/10.1074/jbc.273.27.16816
      We have identified and characterized a novel human cysteine proteinase of the papain family. A full-length cDNA for this enzyme was cloned from a human brain cDNA library. Nucleotide sequence analysis revealed that the isolated cDNA codes for a polypeptide of 303 amino acids, tentatively called cathepsin Z, that exhibits structural features characteristic of cysteine proteinases. Fluorescent in situ hybridization experiments revealed that the human cathepsin Z gene maps to chromosome 20q13, a location that differs from all cysteine proteinase genes mapped to date. The cDNA encoding cathepsin Z was expressed inEscherichia coli as a fusion protein with glutathioneS-transferase, and after purification, the recombinant protein was able to degrade the synthetic peptide benzyloxycarbonyl-Phe-Arg-7-amido-4-methylcoumarin, used as a substrate for cysteine proteinases. Northern blot analysis demonstrated that cathepsin Z is widely expressed in human tissues, suggesting that this enzyme could be involved in the normal intracellular protein degradation taking place in all cell types. Cathepsin Z is also ubiquitously distributed in cancer cell lines and in primary tumors from different sources, suggesting that this enzyme may participate in tumor progression as reported for other cathepsins. Finally, on the basis of a series of distinctive structural features, including diverse peptide insertions and an unusual short propeptide, together with its unique chromosomal location among cysteine proteinases, we propose that cathepsin Z may be the first representative of a novel subfamily of this class of proteolytic enzymes.
      The cysteine proteinases belonging to the papain family represent a major component of the lysosomal proteolytic system and play an essential role in protein degradation and turnover (
      • Bond J.S.
      • Butler P.E.
      ,
      • Chapman H.A.
      • Riese R.J.
      • Shi G.P.
      ). In addition, these proteolytic enzymes appear to play an extracellular role in a number of normal and pathological conditions including bone remodeling (
      • Tezuka K.
      • Tezuka Y.
      • Maejima A.
      • Sato T.
      • Nemoto K.
      • Kamioka H.
      • Hakeda Y.
      • Kumegawa M.
      ), prohormone activation (
      • Krieger T.J.
      • Hook V.Y.H.
      ), rheumatoid arthritis (
      • Mort J.S.
      • Recklies A.D.
      • Poole A.R.
      ), Alzheimer's disease (
      • Golde T.E.
      • Estus S.
      • Younkin L.H.
      • Selkoe D.J.
      • Younkin S.G.
      ), pulmonary emphysema (
      • Mason R.W.
      • Johnson D.A.
      • Barrett A.J.
      • Chapman H.A.
      ), and cancer invasion and metastasis (
      • Sloane B.F.
      ). To date, nine human cysteine proteinases of the papain family have been isolated and characterized at the amino acid sequence level: cathepsin B (
      • Chan S.J.
      • San Segundo B.
      • McCormick M.B.
      • Steiner D.F.
      ), cathepsin L (
      • Gal S.
      • Gottesman M.M.
      ,
      • Joseph L.J.
      • Chang L.C.
      • Stamenkovich D.
      • Sukhatme V.P.
      ), cathepsin H (
      • Fuchs R.
      • Machleidt W.
      • Gassen H.G.
      ,
      • Ritonja A.
      • Popovic T.
      • Kotnik M.
      • Machleidt W.
      • Turk V.
      ), cathepsin S (
      • Wiederanders B.
      • Brömme D.
      • Kirschke H.
      • von Figura K.
      • Schmidt B.
      • Peters C.
      ,
      • Shi G.P.
      • Munger J.S.
      • Meara J.P.
      • Rich D.H.
      • Chapman H.A.
      ), cathepsin C (
      • Paris A.
      • Strukelj B.
      • Pungercar J.
      • Renko M.
      • Dolenc I.
      • Turk V.
      ), cathepsin O (
      • Velasco G.
      • Ferrando A.A.
      • Puente X.A.
      • Sánchez L.M.
      • López-Otı́n C.
      ), cathepsin K (
      • Inaoka T.
      • Bilbe G.
      • Ishibashi O.
      • Tezuka K.
      • Kumegawa M.
      • Kokubo T.
      ,
      • Bromme D.
      • Okamoto K.
      • Wang B.B.
      • Biroc S.
      ), cathepsin W (
      • Linnevers C.
      • Smeekens S.P.
      • Bromme D.
      ), and cathepsin L2 (
      • Santamarı́a I
      • Velasco G.
      • Cazorla M.
      • Fueyo A.
      • Campo E.
      • López-Otı́n C.
      ). All of them contain an essential cysteine residue in their active site but differ in tissue distribution and in some enzymatic properties, including substrate specificities and pH stability. Furthermore, several groups have reported the existence of additional cysteine proteinases including cathepsins M, N, P, and T, which were originally identified because of their degrading activity on specific substrates such as aldolase, collagen, proinsulin, or tyrosine aminotransferase, but whose characterization at the molecular level has not yet been reported (
      • Pontremoli S.
      • Melloni E.
      • Salamino F.
      • Sparatore B.
      • Michetti M.
      • Horecker B.L.
      ,
      • Maciewicz R.
      • Etherington D.
      ,
      • Docherty K.
      • Carroll R.J.
      • Steiner D.F.
      ,
      • Gohda E.
      • Pitot H.C.
      ).
      According to structural and functional data, it is well established that the different cysteine proteinases of the papain family are synthesized as preproenzymes, which are processed to the corresponding proenzymes and targeted to the lysosomes by the mannose 6-phosphate signal attached to them. The enzymes are further processed to mature forms consisting of either a single polypeptide chain or a two-chain form composed of heavy and light chains linked by a disulfide bond (
      • Berti P.J.
      • Storer A.C.
      ). However, in some cases, the precursors of these lysosomal enzymes escape from this processing pathway and continue along the secretory route, entering storage granules and being finally released into the extracellular space (
      • Kornfeld S.
      • Mellman I.
      ). In fact, a series of reports have shown that several lysosomal cysteine proteinases are released by tumor cells from different sources, supporting the concept that secreted lysosomal enzymes may play important roles in the developmnent of malignant processes (
      • Sloane B.F.
      • Dunn J.R.
      • Honn K.V.
      ,
      • Recklies A.D.
      • Poole A.R.
      • Mort J.S.
      ,
      • Gal S.
      • Gottesman M.M.
      ). Furthermore, lysosomal cysteine proteinases have been found to be secreted by activated macrophages, by osteoclasts, or by fibroblasts from patients with I-cell disease, thereby extending the pattern of physiological and pathological conditions in which these enzymes may be involved (
      • Chapman H.A.
      • Riese R.J.
      • Shi G.P.
      ,
      • Kornfeld S.
      • Mellman I.
      ). Based on the hypothesis that a number of different cysteine proteinases could be responsible for the wide variety of biological functions ascribed to this protein family, we have been interested in examining the possibility that additional yet uncharacterized family members could be produced by human tissues. This search for new human cysteine proteinases led us to identify cathepsin O, originally cloned from a breast carcinoma but widely distributed in human tissues (
      • Velasco G.
      • Ferrando A.A.
      • Puente X.A.
      • Sánchez L.M.
      • López-Otı́n C.
      ). We have also described the cloning and characterization of human bleomycin hydrolase, a cytosolic cysteine proteinase distantly related to other members of the papain family and involved in chemotherapy resistance (
      • Ferrando A.A.
      • Velasco G.
      • Campo E.
      • López-Otı́n C.
      ,
      • Ferrando A.A.
      • Pendás A.M.
      • Llano E.
      • Velasco G.
      • Lidereau R.
      • López-Otı́n C.
      ). Finally, we have recently reported the finding of cathepsin L2, a cysteine proteinase structurally related to cathepsin L, but showing a unique tissue distribution (
      • Santamarı́a I
      • Velasco G.
      • Cazorla M.
      • Fueyo A.
      • Campo E.
      • López-Otı́n C.
      ). In this study, we report the identification, chromosomal location, and structural and enzymatic characterization of a novel member of this family of enzymes, which has been tentatively called cathepsin Z.

      DISCUSSION

      In this work we report the identification of a novel human cysteine proteinase called cathepsin Z. We also provide a structural and functional analysis of this novel enzyme and describe its pattern of expression in normal and tumor tissues. Finally, we establish the chromosomal location of the cathepsin Z gene in the human genome, with the finding that it maps to chromosome 20, which is a unique location for any human cysteine proteinase mapped to date.
      The identification of cathepsin Z was initially based on a search of the human EST data base looking for sequences with similarity to previously characterized cysteine proteinases. The identified sequences were then PCR-amplified and used to screen cDNA libraries from different human tissues. This strategy led finally to the isolation of a full-length cDNA coding for a protein with sequence similarity to human cysteine proteinases of the papain family, which was tentatively called cathepsin Z. The identified sequence for this novel enzyme exhibits the domain structure characteristic of cysteine proteinases, including a signal sequence, a prodomain, and a catalytic domain responsible for the proteolytic activity of these proteins (
      • Berti P.J.
      • Storer A.C.
      ). It also contains a series of residues proposed to be important in the catalytic mechanism of these enzymes such as the active site Cys residue which is transiently acetylated during peptide hydrolysis, as well as the Asn and His residues which form the catalytic triad of cysteine proteinases (
      • Kamphuis I.G.
      • Drenth J.
      • Baker E.N.
      ,
      • Musil D.
      • Zucic D.
      • Turk D.
      • Engh R.A.
      • Mayr I.
      • Huber R.
      • Popovic T.
      • Turk V.
      • Towatari T.
      • Katunuma N.
      • Bode W.
      ,
      • Coulombe R.
      • Grochulski P.
      • Sivaraman J.
      • Ménard R.
      • Mort J.S.
      • Cygler M.
      ). However, a more detailed structural analysis of the sequence determined for cathepsin Z revealed some specific features for this novel enzyme. Thus, this novel cysteine proteinase contains three peptide insertions unique among all family members (Fig. 2). The first of these insertions consists of the introduction of the tripeptide (His-Ile-Pro) immediately adjacent to the Gln residue of the oxyanion hole. This insertion is also present in the murine homologue of cathepsin Z
      I. Santamarı́a and C. López-Otı́n, unpublished data.
      , and would considerably increase the short distance (5 residues) separating this Gln residue from the active site Cys of the remaining cysteine proteinases of the papain family. Therefore, it is tempting to speculate that it could confer distinct catalytic properties or affect the substrate specificity of cathepsin Z. The two other insertions consist of an 8-residue peptide located in the middle of the molecule and a 14-residue peptide in the C-terminal end of the molecule, but their putative structural and functional significance on cathepsin Z properties remains unknown. Nevertheless, the most striking feature of the sequence of cathepsin Z is its unusually short propeptide when compared with those present in other cysteine proteinases. It is well known that all cysteine proteinases are synthesized as inactive precursors with an N-terminal propeptide which acts as an intrinsic inhibitor of the proteolytic activity (
      • Fox T.
      • de Miguel E.
      • Mort J.S.
      • Storer A.C.
      ). The propeptide has also found to be essential for correct folding of some cysteine proteinases and for their stabilization upon exposure to changes in pH environments (
      • Tao K.
      • Stearns N.A.
      • Dong J.
      • Wu Q.I.
      • Sahagian G.G.
      ,
      • Carmona E.
      • Dufour E.
      • Plouffe C.
      • Takebe S.
      • Mason P.
      • Mort J.S.
      • Ménard R.
      ). The overall sequence similarities among the propeptides of the different cysteine proteinases are low, but according to structural features, they can be assigned to two groups (
      • Karrer K.M.
      • Peiffer S.L.
      • DiTomas M.E.
      ,
      • Vernet T.
      • Berti P.J.
      • de Montigny C.
      • Musil R.
      • Tessier D.C.
      • Ménard R.
      • Magny M.C.
      • Storer A.C.
      • Thomas D.Y.
      ). The first group contains cathepsin L-like enzymes with proregions greater than 90 amino acids in length and two highly conserved motifs called ERFNIN and GNFD. The second group comprises the cathepsins B from different sources and is characterized by a smaller proregion of about 60 amino acids lacking the ERFNIN motif. However, the proregion of cathepsin Z cannot be assigned to any of these groups because it is only 41 residues in length and lacks both conserved domains. Furthermore, this propeptide sequence does not contain any lysine residue, despite the fact that lysine-based structures present in the proregion of different cathepsins have been proposed to act as the recognition sites for the mannose phosphorylation required for intracellular targeting of these proteins (
      • Cuozzo J.W.
      • Tao K.
      • Wu Q.
      • Young W.
      • Sahagian G.G.
      ). Taking together these structural data, it seems clear that the proregion of cathepsin Z markedly deviates from those of all previously characterized family members, suggesting that it could be a member of a different subfamily of enzymes. Consistent with this hypothesis, chromosomal location of the cathepsin Z gene has revealed that it maps to chromosome 20. This position differs from those reported for the remaining cysteine proteinase genes of the papain family (
      • Shi G.
      • Webb A.C.
      • Foster K.E.
      • Knoll J.H.M.
      • Lemere C.A.
      • Munger J.S.
      • Chapman H.A.
      ,
      • Rood J.A.
      • Van Horn S.
      • Drake F.H.
      • Gowen M.
      • Debouck C.
      ,
      • Santamarı́a I.
      • Pendás A.M.
      • Velasco G.
      • López-Otı́n C.
      ,
      • Chauhan S.S.
      • Popescu N.C.
      • Ray D.
      • Fleischmann R.
      • Gottesman M.M.
      • Troen B.R.
      ,
      • Gong Q.
      • Chan S.J.
      • Bajkowski A.S.
      • Steiner D.F.
      • Frankfater A.
      ,
      • Rao N.V.
      • Rao G.V.
      • Hoidal J.R.
      ,
      • Wang X.
      • Chan S.J.
      • Eddy R.L.
      • Byers M.G.
      • Fukushima Y.
      • Henry W.M.
      • Haley L.L.
      • Steiner D.F.
      • Shows T.B.
      ), providing additional support to the above structural data that suggest that this novel cysteine proteinase is not closely related to the other members of the papain family. In addition to its possible value in the context of evolutionary studies of the human cysteine proteinases, knowledge of the chromosomal location of the cathepsin Z gene may be useful in searching for putative diseases related to abnormalities in this protein, as already demonstrated for cathepsin K (
      • Gelb B.D.
      • Shi G.P.
      • Chapman H.A.
      • Desnick R.J.
      ).
      In this work we have also provided evidence that cathepsin Z is expressed in all normal tissues analyzed, which suggests a putative general role of this protein as a proteolytic enzyme involved in the normal intracellular protein turnover taking place in all cell types. This housekeeping role of cathepsin Z in human tissues would be similar to that proposed for cathepsins B, L, H, and O, but distinguishes this enzyme from a series of recently described cysteine proteinases which appear to play highly specific roles in those tissues in which they are overexpressed or even exclusively expressed. This is the case of cathepsins K, S, W, and L2, predominantly expressed in osteoclasts, lymphatic tissues, T-lymphocytes, and thymus and testis, respectively, and proposed to be involved in bone remodeling (cathepsin K), antigen presentation (cathepsin S), regulation of T-cell cytolytic activity (cathepsin W), and regulation of the immune response and fertilization processes (cathepsin L2) (
      • Linnevers C.
      • Smeekens S.P.
      • Bromme D.
      ,
      • Santamarı́a I
      • Velasco G.
      • Cazorla M.
      • Fueyo A.
      • Campo E.
      • López-Otı́n C.
      ,
      • Gelb B.D.
      • Shi G.P.
      • Chapman H.A.
      • Desnick R.J.
      ,
      • Riese R.J.
      • Wolff P.R.
      • Brömme D.
      • Natkin L.R
      • Villadangos J.A.
      • Ploegh H.L.
      • Chapman H.A.
      ). The expression analysis of cathepsin Z also revealed a ubiquitous presence of this enzyme in a series of human cancer cell lines and primary tumors from different sources. This finding suggests that cathepsin Z may be somewhat linked to the malignant transformation of human cells as already shown for other cysteine proteinases (
      • Sloane B.F.
      ,
      • Chauhan S.S.
      • Goldstein L.J.
      • Gottesman M.M.
      ) and adds a new interest to the study of this novel enzyme.
      In summary, according to the results of this work, human cathepsin Z is a novel member of the papain family of cysteine proteinases that shows clear differences with the remaining family members characterized to date. The occurrence of a series of unique features in its structure, including diverse peptide insertions and an unusually short propeptide region, together with its chromosomal location at 20q13, distinguishes this enzyme from other cysteine proteinases and suggests that it may be the first representative of a new cathepsin subfamily. The availability of recombinant cathepsin Z and specific reagents for this proteinase will be very helpful in evaluating the functional significance of these structural differences as well as in studying the potential role of this novel enzyme in the protein degradative processes occurring in normal and pathological conditions, including cancer.

      ACKNOWLEDGEMENTS

      We thank Drs. M. Balbı́n and J. P. Freije for helpful comments and S. Alvarez for excellent technical assistance.

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