Isolation of SPINK6 in Human Skin: Selective Inhibitor of Kallikrein-related Peptidases

Overview

Journal J Biol Chem

Specialty Biochemistry

Date 2010 Jul 30

PMID 20667819

Citations 29

Authors

Ulf Meyer-Hoffert

Zhihong Wu

Tomasz Kantyka

Jan Fischer

Ties Latendorf

Britta Hansmann

Joachim Bartels

Yinghong He

Regine Glaser

Jens-Michael Schroder

Affiliations

Soon will be listed here.

Abstract

Kallikrein-related peptidases (KLKs) play a central role in skin desquamation. They are tightly controlled by specific inhibitors, including the lymphoepithelial Kazal-type inhibitor (LEKTI) encoded by SPINK5 and LEKTI-2 encoded by SPINK9. Herein, we identify SPINK6 as a selective inhibitor of KLKs in the skin. Unlike LEKTI but similar to LEKTI-2, SPINK6 possesses only one typical Kazal domain. Its mRNA was detected to be expressed at low levels in several tissues and was induced during keratinocyte differentiation. Natural SPINK6 was purified from human plantar stratum corneum extracts. Immunohistochemical analyses revealed SPINK6 expression in the stratum granulosum of human skin at various anatomical localizations and in the skin appendages, including sebaceous glands and sweat glands. SPINK6 expression was decreased in lesions of atopic dermatitis. Using KLK5, KLK7, KLK8, KLK14, thrombin, trypsin, plasmin, matriptase, prostasin, mast cell chymase, cathepsin G, neutrophil elastase, and chymotrypsin, inhibition with recombinant SPINK6 was detected only for KLK5, KLK7, and KLK14, with apparent K(i) values of 1.33, 1070, and 0.5 nm, respectively. SPINK6 inhibited desquamation of human plantar callus in an ex vivo model. Our findings suggest that SPINK6 plays a role in modulating the activity of KLKs in human skin. A selective inhibition of KLKs by SPINK6 might have therapeutic potential when KLK activity is elevated.

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References

Borgono C, Michael I, Komatsu N, Jayakumar A, Kapadia R, Clayman G . A potential role for multiple tissue kallikrein serine proteases in epidermal desquamation. J Biol Chem. 2006; 282(6):3640-52. DOI: 10.1074/jbc.M607567200. View

Tatusova T, Madden T . BLAST 2 Sequences, a new tool for comparing protein and nucleotide sequences. FEMS Microbiol Lett. 1999; 174(2):247-50. DOI: 10.1111/j.1574-6968.1999.tb13575.x. View

Meyer-Hoffert U, Wu Z, Schroder J . Identification of lympho-epithelial Kazal-type inhibitor 2 in human skin as a kallikrein-related peptidase 5-specific protease inhibitor. PLoS One. 2009; 4(2):e4372. PMC: 2631147. DOI: 10.1371/journal.pone.0004372. View

Briot A, Deraison C, Lacroix M, Bonnart C, Robin A, Besson C . Kallikrein 5 induces atopic dermatitis-like lesions through PAR2-mediated thymic stromal lymphopoietin expression in Netherton syndrome. J Exp Med. 2009; 206(5):1135-47. PMC: 2715042. DOI: 10.1084/jem.20082242. View

Mitsudo K, Jayakumar A, Henderson Y, Frederick M, Kang Y, Wang M . Inhibition of serine proteinases plasmin, trypsin, subtilisin A, cathepsin G, and elastase by LEKTI: a kinetic analysis. Biochemistry. 2003; 42(13):3874-81. DOI: 10.1021/bi027029v. View

Ishida-Yamamoto A, Deraison C, Bonnart C, Bitoun E, Robinson R, OBrien T . LEKTI is localized in lamellar granules, separated from KLK5 and KLK7, and is secreted in the extracellular spaces of the superficial stratum granulosum. J Invest Dermatol. 2005; 124(2):360-6. DOI: 10.1111/j.0022-202X.2004.23583.x. View

Simon M, Jonca N, Guerrin M, Haftek M, Bernard D, Caubet C . Refined characterization of corneodesmosin proteolysis during terminal differentiation of human epidermis and its relationship to desquamation. J Biol Chem. 2001; 276(23):20292-9. DOI: 10.1074/jbc.M100201200. View

Magert H, Standker L, Kreutzmann P, Zucht H, Reinecke M, Sommerhoff C . LEKTI, a novel 15-domain type of human serine proteinase inhibitor. J Biol Chem. 1999; 274(31):21499-502. DOI: 10.1074/jbc.274.31.21499. View

Ziegler S, Liu Y . Thymic stromal lymphopoietin in normal and pathogenic T cell development and function. Nat Immunol. 2006; 7(7):709-14. DOI: 10.1038/ni1360. View

10.

Brattsand M, Stefansson K, Hubiche T, Nilsson S, Egelrud T . SPINK9: a selective, skin-specific Kazal-type serine protease inhibitor. J Invest Dermatol. 2009; 129(7):1656-65. DOI: 10.1038/jid.2008.448. View

11.

Yousef G, Diamandis E . The new human tissue kallikrein gene family: structure, function, and association to disease. Endocr Rev. 2001; 22(2):184-204. DOI: 10.1210/edrv.22.2.0424. View

12.

Deraison C, Bonnart C, Lopez F, Besson C, Robinson R, Jayakumar A . LEKTI fragments specifically inhibit KLK5, KLK7, and KLK14 and control desquamation through a pH-dependent interaction. Mol Biol Cell. 2007; 18(9):3607-19. PMC: 1951746. DOI: 10.1091/mbc.e07-02-0124. View

13.

Stefansson K, Brattsand M, Roosterman D, Kempkes C, Bocheva G, Steinhoff M . Activation of proteinase-activated receptor-2 by human kallikrein-related peptidases. J Invest Dermatol. 2007; 128(1):18-25. DOI: 10.1038/sj.jid.5700965. View

14.

Caubet C, Jonca N, Brattsand M, Guerrin M, Bernard D, Schmidt R . Degradation of corneodesmosome proteins by two serine proteases of the kallikrein family, SCTE/KLK5/hK5 and SCCE/KLK7/hK7. J Invest Dermatol. 2004; 122(5):1235-44. DOI: 10.1111/j.0022-202X.2004.22512.x. View

15.

Ishida-Yamamoto A, Simon M, Kishibe M, Miyauchi Y, Takahashi H, Yoshida S . Epidermal lamellar granules transport different cargoes as distinct aggregates. J Invest Dermatol. 2004; 122(5):1137-44. DOI: 10.1111/j.0022-202X.2004.22515.x. View

16.

Hansson L, Backman A, Ny A, Edlund M, Ekholm E, Ekstrand Hammarstrom B . Epidermal overexpression of stratum corneum chymotryptic enzyme in mice: a model for chronic itchy dermatitis. J Invest Dermatol. 2002; 118(3):444-9. DOI: 10.1046/j.0022-202x.2001.01684.x. View

17.

Wu Z, Meyer-Hoffert U, Reithmayer K, Paus R, Hansmann B, He Y . Highly complex peptide aggregates of the S100 fused-type protein hornerin are present in human skin. J Invest Dermatol. 2008; 129(6):1446-58. DOI: 10.1038/jid.2008.370. View

18.

Komatsu N, Suga Y, Saijoh K, Liu A, Khan S, Mizuno Y . Elevated human tissue kallikrein levels in the stratum corneum and serum of peeling skin syndrome-type B patients suggests an over-desquamation of corneocytes. J Invest Dermatol. 2006; 126(10):2338-42. DOI: 10.1038/sj.jid.5700379. View

19.

Sondell B, Thornell L, Egelrud T . Evidence that stratum corneum chymotryptic enzyme is transported to the stratum corneum extracellular space via lamellar bodies. J Invest Dermatol. 1995; 104(5):819-23. DOI: 10.1111/1523-1747.ep12607007. View

20.

Shaw J, Diamandis E . Distribution of 15 human kallikreins in tissues and biological fluids. Clin Chem. 2007; 53(8):1423-32. DOI: 10.1373/clinchem.2007.088104. View