Abstract
Kallikrein-related peptidases KLK5, KLK7 and KLK14 are important proteases in skin desquamation and aberrant KLK activity is associated with inflammatory skin diseases such as Netherton syndrome but also with various serious forms of cancer. Previously, we have identified KLK7 as the first protease target of vaspin (Serpin A12). Here, we report KLK14 as a second KLK protease to be inhibited by vaspin. In conclusion, vaspin represents a multi-specific serpin targeting the kallikrein proteases KLK7 and KLK14, with distinct exosites regulating recognition of these target proteases and opposing effects of heparin binding on the inhibition reaction.
Acknowledgments
The vaspin expression plasmid was a kind gift of Dr. J. Wada (Department of Medicine and Clinical Science Okayama University Graduate School of Medicine, Okayama, Japan). This work was funded by grants of the Deutsche Forschungsgemeinschaft SFB1052, ‘Obesity Mechanisms’ (Funder Id: 10.13039/501100001659, C4 NS, C7 JTH).
Conflict of interest statement: The authors declare that they have no conflicts of interest regarding the contents of this article.
References
Chen, V.C., Chao, L., and Chao, J. (2000). A positively charged loop on the surface of kallistatin functions to enhance tissue kallikrein inhibition by acting as a secondary binding site for kallikrein. J. Biol. Chem. 275, 40371–40377.10.1074/jbc.M005691200Search in Google Scholar
Chen, V.C., Chao, L., Pimenta, D.C., Bledsoe, G., Juliano, L., and Chao, J. (2001). Identification of a major heparin-binding site in kallistatin. J. Biol. Chem. 276, 1276–1284.10.1074/jbc.M005791200Search in Google Scholar
de Veer, S.J., Furio, L., Swedberg, J.E., Munro, C.A., Brattsand, M., Clements, J.A., Hovnanian, A., and Harris, J.M. (2017). Selective substrates and inhibitors for kallikrein-related peptidase 7 (KLK7) shed light on KLK proteolytic activity in the stratum corneum. J. Invest. Dermatol. 137, 430–439.10.1016/j.jid.2016.09.017Search in Google Scholar
Debela, M., Magdolen, V., Schechter, N., Valachova, M., Lottspeich, F., Craik, C.S., Choe, Y., Bode, W., and Goettig, P. (2006). Specificity profiling of seven human tissue kallikreins reveals individual subsite preferences. J. Biol. Chem. 281, 25678–25688.10.1074/jbc.M602372200Search in Google Scholar
Egelrud, T. and Lundstrom, A. (1991). A chymotrypsin-like proteinase that may be involved in desquamation in plantar stratum corneum. Arch. Dermatol. Res. 283, 108–112.10.1007/BF00371618Search in Google Scholar
Ekholm, E. and Egelrud, T. (1999). Stratum corneum chymotryptic enzyme in psoriasis. Arch. Dermatol. Res. 291, 195–200.10.1007/s004030050393Search in Google Scholar
Felber, L.M., Borgono, C.A., Cloutier, S.M., Kundig, C., Kishi, T., Ribeiro Chagas, J., Jichlinski, P., Gygi, C.M., Leisinger, H.J., Diamandis, E.P., et al. (2005). Enzymatic profiling of human kallikrein 14 using phage-display substrate technology. Biol. Chem. 386, 291–298.10.1515/BC.2005.035Search in Google Scholar
Felber, L.M., Kundig, C., Borgono, C.A., Chagas, J.R., Tasinato, A., Jichlinski, P., Gygi, C.M., Leisinger, H.J., Diamandis, E.P., Deperthes, D., et al. (2006). Mutant recombinant serpins as highly specific inhibitors of human kallikrein 14. FEBS J. 273, 2505–2514.10.1111/j.1742-4658.2006.05257.xSearch in Google Scholar
Heiker, J.T. (2014). Vaspin (serpinA12) in obesity, insulin resistance, and inflammation. J. Pept. Sci. 20, 299–306.10.1002/psc.2621Search in Google Scholar
Heiker, J.T., Kloting, N., Kovacs, P., Kuettner, E.B., Strater, N., Schultz, S., Kern, M., Stumvoll, M., Bluher, M., and Beck-Sickinger, A.G. (2013). Vaspin inhibits kallikrein 7 by serpin mechanism. Cell. Mol. Life Sci. 70, 2569–2583.10.1007/s00018-013-1258-8Search in Google Scholar
Hida, K., Wada, J., Eguchi, J., Zhang, H., Baba, M., Seida, A., Hashimoto, I., Okada, T., Yasuhara, A., Nakatsuka, A., et al. (2005). Visceral adipose tissue-derived serine protease inhibitor: a unique insulin-sensitizing adipocytokine in obesity. Proc. Natl. Acad. Sci. USA 102, 10610–10615.10.1073/pnas.0504703102Search in Google Scholar
Kasparek, P., Ileninova, Z., Zbodakova, O., Kanchev, I., Benada, O., Chalupsky, K., Brattsand, M., Beck, I.M., and Sedlacek, R. (2017). KLK5 and KLK7 ablation fully rescues lethality of Netherton syndrome-like phenotype. PLoS Genet. 13, e1006566.10.1371/journal.pgen.1006566Search in Google Scholar
Komatsu, N., Tsai, B., Sidiropoulos, M., Saijoh, K., Levesque, M.A., Takehara, K., and Diamandis, E.P. (2006). Quantification of eight tissue kallikreins in the stratum corneum and sweat. J. Invest. Dermatol. 126, 925–929.10.1038/sj.jid.5700146Search in Google Scholar
Koskimaki, J.E., Rosca, E.V., Rivera, C.G., Lee, E., Chen, W., Pandey, N.B., and Popel, A.S. (2012). Serpin-derived peptides are antiangiogenic and suppress breast tumor xenograft growth. Transl. Oncol. 5, 92–97.10.1593/tlo.11244Search in Google Scholar
Luo, L.Y. and Jiang, W. (2006). Inhibition profiles of human tissue kallikreins by serine protease inhibitors. Biol. Chem. 387, 813–816.10.1515/BC.2006.103Search in Google Scholar
Mast, A.E., Enghild, J.J., Pizzo, S.V., and Salvesen, G. (1991). Analysis of the plasma elimination kinetics and conformational stabilities of native, proteinase-complexed, and reactive site cleaved serpins: comparison of α1-proteinase inhibitor, α1-antichymotrypsin, antithrombin III, α2-antiplasmin, angiotensinogen, and ovalbumin. Biochemistry 30, 1723–1730.10.1021/bi00220a039Search in Google Scholar
Nakatsuka, A., Wada, J., Iseda, I., Teshigawara, S., Higashio, K., Murakami, K., Kanzaki, M., Inoue, K., Terami, T., Katayama, A., et al. (2012). Vaspin is an adipokine ameliorating ER stress in obesity as a ligand for cell-surface GRP78/MTJ-1 complex. Diabetes 61, 2823–2832.10.2337/db12-0232Search in Google Scholar
Oertwig, K., Ulbricht, D., Hanke, S., Pippel, J., Bellmann-Sickert, K., Strater, N., and Heiker, J.T. (2017). Glycosylation of human vaspin (SERPINA12) and its impact on serpin activity, heparin binding and thermal stability. Biochim. Biophys. Acta 1865, 1188–1194.10.1016/j.bbapap.2017.06.020Search in Google Scholar
Pippel, J., Kuettner, E.B., Ulbricht, D., Daberger, J., Schultz, S., Heiker, J.T., and Strater, N. (2016). Crystal structure of cleaved vaspin (serpinA12). Biol. Chem. 397, 111–123.10.1515/hsz-2015-0229Search in Google Scholar
Pizzo, S.V., Mast, A.E., Feldman, S.R., and Salvesen, G. (1988). In vivo catabolism of alpha 1-antichymotrypsin is mediated by the Serpin receptor which binds alpha 1-proteinase inhibitor, antithrombin III and heparin cofactor II. Biochim. Biophys. Acta 967, 158–162.10.1016/0304-4165(88)90005-0Search in Google Scholar
Schultz, S., Saalbach, A., Heiker, J.T., Meier, R., Zellmann, T., Simon, J.C., and Beck-Sickinger, A.G. (2013). Proteolytic activation of prochemerin by kallikrein 7 breaks an ionic linkage and results in C-terminal rearrangement. Biochem. J. 452, 271–280.10.1042/BJ20121880Search in Google Scholar
Stratikos, E. and Gettins, P.G. (1999). Formation of the covalent serpin-proteinase complex involves translocation of the proteinase by more than 70 Å and full insertion of the reactive center loop into β-sheet A. Proc. Natl. Acad. Sci. USA 96, 4808–4813.10.1073/pnas.96.9.4808Search in Google Scholar
Uhlén, M., Fagerberg, L., Hallström, B.M., Lindskog, C., Oksvold, P., Mardinoglu, A., Sivertsson, Å., Kampf, C., Sjostedt, E., Asplund, A., et al. (2015). Tissue-based map of the human proteome. Science 347, 1260419.10.1126/science.1260419Search in Google Scholar
Ulbricht, D., Pippel, J., Schultz, S., Meier, R., Strater, N., and Heiker, J.T. (2015). A unique serpin P1′ glutamate and a conserved β-sheet C arginine are key residues for activity, protease recognition and stability of serpinA12 (vaspin). Biochem. J. 470, 357–367.10.1042/BJ20150643Search in Google Scholar
Ulbricht, D., Oertwig, K., Arnsburg, K., Saalbach, A., Pippel, J., Strater, N., and Heiker, J.T. (2017). Basic residues of β-sheet A contribute to heparin binding and activation of vaspin (serpin A12). J. Biol. Chem. 292, 994–1004.10.1074/jbc.M116.748020Search in Google Scholar
Yamasaki, K., Di Nardo, A., Bardan, A., Murakami, M., Ohtake, T., Coda, A., Dorschner, R.A., Bonnart, C., Descargues, P., Hovnanian, A., et al. (2007). Increased serine protease activity and cathelicidin promotes skin inflammation in rosacea. Nat. Med. 13, 975–980.10.1038/nm1616Search in Google Scholar
Zieger, K., Weiner, J., Kunath, A., Gericke, M., Krause, K., Kern, M., Stumvoll, M., Kloting, N., Bluher, M., and Heiker, J.T. (2017). Ablation of kallikrein 7 (KLK7) in adipose tissue ameliorates metabolic consequences of high fat diet-induced obesity by counteracting adipose tissue inflammation in vivo. Cell. Mol. Life Sci. 75, 727–774.10.1007/s00018-017-2658-ySearch in Google Scholar
Supplementary Material:
The online version of this article offers supplementary material (https://doi.org/10.1515/hsz-2018-0108).
©2018 Walter de Gruyter GmbH, Berlin/Boston
