Abstract
Deficiency in the serine protease inhibitor LEKTI is the etiological origin of Netherton syndrome, which causes detachment of the stratum corneum and chronic inflammation. Here we show that the membrane protease matriptase initiates Netherton syndrome in a LEKTI-deficient mouse model by premature activation of a pro-kallikrein cascade. Auto-activation of pro-inflammatory pro-kallikrein-related peptidases that are associated with stratum corneum detachment was either low or undetectable, but they were efficiently activated by matriptase. Ablation of matriptase from LEKTI-deficient mice dampened inflammation, eliminated aberrant protease activity, prevented detachment of the stratum corneum, and improved the barrier function of the epidermis. These results uncover a pathogenic matriptase–pro-kallikrein pathway that could operate in several human skin and inflammatory diseases.
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References
Caubet, C. et al. Degradation of corneodesmosome proteins by two serine proteases of the kallikrein family, SCTE/KLK5/hK5 and SCCE/KLK7/hK7. J. Invest. Dermatol. 122, 1235–1244 (2004).
Brattsand, M. & Egelrud, T. Purification, molecular cloning, and expression of a human stratum corneum trypsin-like serine protease with possible function in desquamation. J. Biol. Chem. 274, 30033–30040 (1999).
Hansson, L. et al. Cloning, expression, and characterization of stratum corneum chymotryptic enzyme. A skin-specific human serine proteinase. J. Biol. Chem. 269, 19420–19426 (1994).
Descargues, P. et al. Spink5-deficient mice mimic Netherton syndrome through degradation of desmoglein 1 by epidermal protease hyperactivity. Nat. Genet. 37, 56–65 (2005).
Hewett, D.R. et al. Lethal, neonatal ichthyosis with increased proteolytic processing of filaggrin in a mouse model of Netherton syndrome. Hum. Mol. Genet. 14, 335–346 (2005).
Yang, T. et al. Epidermal detachment, desmosomal dissociation, and destabilization of corneodesmosin in Spink5−/− mice. Genes Dev. 18, 2354–2358 (2004).
Deraison, C. et al. LEKTI fragments specifically inhibit KLK5, KLK7, and KLK14 and control desquamation through a pH-dependent interaction. Mol. Biol. Cell 18, 3607–3619 (2007).
Hachem, J.P. et al. Serine protease activity and residual LEKTI expression determine phenotype in Netherton syndrome. J. Invest. Dermatol. 126, 1609–1621 (2006).
Stefansson, K., Brattsand, M., Ny, A., Glas, B. & Egelrud, T. Kallikrein-related peptidase 14 may be a major contributor to trypsin-like proteolytic activity in human stratum corneum. Biol. Chem. 387, 761–768 (2006).
Suzuki, Y., Nomura, J., Koyama, J. & Horii, I. The role of proteases in stratum corneum: involvement in stratum corneum desquamation. Arch. Dermatol. Res. 286, 249–253 (1994).
Komatsu, N. et al. Elevated stratum corneum hydrolytic activity in Netherton syndrome suggests an inhibitory regulation of desquamation by SPINK5-derived peptides. J. Invest. Dermatol. 118, 436–443 (2002).
Descargues, P. et al. Corneodesmosomal cadherins are preferential targets of stratum corneum trypsin- and chymotrypsin-like hyperactivity in Netherton syndrome. J. Invest. Dermatol. 126, 1622–1632 (2006).
Chavanas, S. et al. Mutations in SPINK5, encoding a serine protease inhibitor, cause Netherton syndrome. Nat. Genet. 25, 141–142 (2000).
Smith, D.L., Smith, J.G., Wong, S.W. & deShazo, R.D. Netherton's syndrome. Br. J. Dermatol. 133, 153–154 (1995).
Smith, D.L., Smith, J.G., Wong, S.W. & deShazo, R.D. Netherton's syndrome: a syndrome of elevated IgE and characteristic skin and hair findings. J. Allergy Clin. Immunol. 95, 116–123 (1995).
Bitoun, E. et al. Netherton syndrome: disease expression and spectrum of SPINK5 mutations in 21 families. J. Invest. Dermatol. 118, 352–361 (2002).
Chavanas, S. et al. Localization of the Netherton syndrome gene to chromosome 5q32, by linkage analysis and homozygosity mapping. Am. J. Hum. Genet. 66, 914–921 (2000).
Mägert, H.J. et al. LEKTI, a novel 15-domain type of human serine proteinase inhibitor. J. Biol. Chem. 274, 21499–21502 (1999).
Schechter, N.M. et al. Inhibition of human kallikreins 5 and 7 by the serine protease inhibitor lympho-epithelial Kazal-type inhibitor (LEKTI). Biol. Chem. 386, 1173–1184 (2005).
Briot, A. et al. Kallikrein 5 induces atopic dermatitis-like lesions through PAR2-mediated thymic stromal lymphopoietin expression in Netherton syndrome. J. Exp. Med. 206, 1135–1147 (2009).
Hachem, J.P. et al. Sustained serine proteases activity by prolonged increase in pH leads to degradation of lipid processing enzymes and profound alterations of barrier function and stratum corneum integrity. J. Invest. Dermatol. 125, 510–520 (2005).
Brattsand, M., Stefansson, K., Lundh, C., Haasum, Y. & Egelrud, T. A proteolytic cascade of kallikreins in the stratum corneum. J. Invest. Dermatol. 124, 198–203 (2005).
Takeuchi, T. et al. Cellular localization of membrane-type serine protease 1 and identification of protease-activated receptor-2 and single-chain urokinase-type plasminogen activator as substrates. J. Biol. Chem. 275, 26333–26342 (2000).
Lee, S.L., Dickson, R.B. & Lin, C.Y. Activation of hepatocyte growth factor and urokinase/plasminogen activator by matriptase, an epithelial membrane serine protease. J. Biol. Chem. 275, 36720–36725 (2000).
Kitamoto, Y., Yuan, X., Wu, Q., McCourt, D.W. & Sadler, J.E. Enterokinase, the initiator of intestinal digestion, is a mosaic protease composed of a distinctive assortment of domains. Proc. Natl. Acad. Sci. USA 91, 7588–7592 (1994).
List, K., Szabo, R., Molinolo, A., Nielsen, B.S. & Bugge, T.H. Delineation of matriptase protein expression by enzymatic gene trapping suggests diverging roles in barrier function, hair formation, and squamous cell carcinogenesis. Am. J. Pathol. 168, 1513–1525 (2006).
Netzel-Arnett, S. et al. Evidence for a matriptase-prostasin proteolytic cascade regulating terminal epidermal differentiation. J. Biol. Chem. 281, 32941–32945 (2006).
Kilpatrick, L.M. et al. Initiation of plasminogen activation on the surface of monocytes expressing the type II transmembrane serine protease matriptase. Blood 108, 2616–2623 (2006).
Alef, T. et al. Ichthyosis, follicular atrophoderma, and hypotrichosis caused by mutations in ST14 is associated with impaired profilaggrin processing. J. Invest. Dermatol. 129, 862–869 (2009).
Ovaere, P., Lippens, S., Vandenabeele, P. & Declercq, W. The emerging roles of serine protease cascades in the epidermis. Trends Biochem. Sci. 34, 453–463 (2009).
Chen, L.M. et al. Prostasin attenuates inducible nitric oxide synthase expression in lipopolysaccharide-induced urinary bladder inflammation. Am. J. Physiol. Renal Physiol. 291, F567–F577 (2006).
List, K. et al. Epithelial integrity is maintained by a matriptase-dependent proteolytic pathway. Am. J. Pathol. 175, 1453–1463 (2009).
List, K. et al. Loss of proteolytically processed filaggrin caused by epidermal deletion of Matriptase/MT-SP1. J. Cell Biol. 163, 901–910 (2003).
Kamata, Y. et al. Neutral cysteine protease bleomycin hydrolase is essential for the breakdown of deiminated filaggrin into amino acids. J. Biol. Chem. 284, 12829–12836 (2009).
Denecker, G. et al. Caspase-14 protects against epidermal UVB photodamage and water loss. Nat. Cell Biol. 9, 666–674 (2007).
Marttin, E., Neelissen-Subnel, M.T., De Haan, F.H. & Bodde, H.E. A critical comparison of methods to quantify stratum corneum removed by tape stripping. Skin Pharmacol. 9, 69–77 (1996).
Dreher, F. et al. Colorimetric method for quantifying human stratum corneum removed by adhesive-tape stripping. Acta Derm. Venereol. 78, 186–189 (1998).
List, K. Matriptase: a culprit in cancer? Future Oncol. 5, 97–104 (2009).
Borgoño, C.A. et al. A potential role for multiple tissue kallikrein serine proteases in epidermal desquamation. J. Biol. Chem. 282, 3640–3652 (2007).
Kishi, K. et al. Characterization of a membrane-bound arginine-specific serine protease from rat intestinal mucosa. J. Biochem. 130, 425–430 (2001).
Smith, F.J. et al. Loss-of-function mutations in the gene encoding filaggrin cause ichthyosis vulgaris. Nat. Genet. 38, 337–342 (2006).
Sandilands, A., Sutherland, C., Irvine, A.D. & McLean, W.H. Filaggrin in the frontline: role in skin barrier function and disease. J. Cell Sci. 122, 1285–1294 (2009).
Ramsay, A.J. et al. Kallikrein-related peptidase 4 (KLK4) initiates intracellular signaling via protease-activated receptors (PARs). KLK4 and PAR-2 are co-expressed during prostate cancer progression. J. Biol. Chem. 283, 12293–12304 (2008).
Hollenberg, M.D. et al. Kallikreins and proteinase-mediated signaling: proteinase-activated receptors (PARs) and the pathophysiology of inflammatory diseases and cancer. Biol. Chem. 389, 643–651 (2008).
Cheng, M.F. et al. Matriptase expression in the normal and neoplastic mast cells. Eur. J. Dermatol. 17, 375–380 (2007).
Oberst, M.D. et al. Characterization of matriptase expression in normal human tissues. J. Histochem. Cytochem. 51, 1017–1025 (2003).
List, K. et al. Deregulated matriptase causes ras-independent multistage carcinogenesis and promotes ras-mediated malignant transformation. Genes Dev. 19, 1934–1950 (2005).
List, K. et al. Matriptase/MT-SP1 is required for postnatal survival, epidermal barrier function, hair follicle development, and thymic homeostasis. Oncogene 21, 3765–3779 (2002).
Szabo, R. et al. Potent inhibition and global co-localization implicate the transmembrane Kunitz-type serine protease inhibitor hepatocyte growth factor activator inhibitor-2 in the regulation of epithelial matriptase activity. J. Biol. Chem. 283, 29495–29504 (2008).
Acknowledgements
We thank D. Martin, L. Fisher and L. Wahl for technical assistance, and J. Silvio Gutkind and M. J. Danton for reviewing this manuscript. Support for this study was provided by the NIDCR Intramural Research Program.
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K.U.S. generated recombinant proteins, performed biochemical experiments and analyzed mice with the assistance of K.L. and R.S. A.L.B. and A.L.R. performed mouse breeding and genotyping. A.M. and R.W. helped to conduct confocal fluorescence microscopy analysis. P.A.O. and T.H.B. designed and supervised the study.
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Sales, K., Masedunskas, A., Bey, A. et al. Matriptase initiates activation of epidermal pro-kallikrein and disease onset in a mouse model of Netherton syndrome. Nat Genet 42, 676–683 (2010). https://doi.org/10.1038/ng.629
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DOI: https://doi.org/10.1038/ng.629
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