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First published online May 4, 2004
doi: 10.1242/10.1242/jcs.01075

Journal of Cell Science 117, 2295-2307 (2004)
Published by The Company of Biologists 2004
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Research Article

Cathepsin D is involved in the regulation of transglutaminase 1 and epidermal differentiation

Friederike Egberts1, Michael Heinrich2, Jens-Michael Jensen1, Supandi Winoto-Morbach2, Stephan Pfeiffer3, Marc Wickel2, Michael Schunck1, Judith Steude2, Paul Saftig4, Ehrhardt Proksch1 and Stefan Schütze2,*

1 Department of Dermatology, University Hospital of Schleswig-Holstein, Campus Kiel, 24105 Kiel, Germany
2 Institute of Immunology, University Hospital of Schleswig-Holstein, Campus Kiel, 24105 Kiel, Germany
3 Central Microscopy, Centrum for Biology, University of Kiel, 24118 Kiel, Germany
4 Department of Biochemistry, University of Kiel, 24118 Kiel, Germany

* Author for correspondence (e-mail: schuetze{at}immunologie.uni-kiel.de)

Accepted 5 January 2004

We previously demonstrated that the aspartate protease cathepsin D is activated by ceramide derived from acid sphingomyelinase. Increased expression of cathepsin D in the skin has been reported in wound healing, psoriasis and skin tumors. We explored specific functions of cathepsin D during epidermal differentiation. Protein expression and enzymatic activity of cathepsin D increased in differentiated keratinocytes in both stratified organotypic cultures and in mouse skin during epidermal barrier repair. Treatment of cultured keratinocytes with exogenous cathepsin D increased the activity of transglutaminase 1, known to cross-link the cornified envelope proteins involucrin and loricrin during epidermal differentiation. Inhibition of cathepsin D by pepstatin A suppressed the activity of transglutaminase 1. Cathepsin D-deficient mice revealed reduced transglutaminase 1 activity and reduced protein levels of the cornified envelope proteins involucrin and loricrin. Also, amount and distribution of cornified envelope proteins involucrin, loricrin, filaggrin, and of the keratins K1 and K5 were significantly altered in cathepsin D-deficient mice. Stratum corneum morphology in cathepsin D-deficient mice was impaired, with increased numbers of corneocyte layers and faint staining of the cornified envelope only, which is similar to the human skin disease lamellar ichthyosis. Our findings suggest a functional link between cathepsin D activation, transglutaminase 1 activity and protein expression of cornified envelope proteins during epidermal differentiation.

Key words: Barrier function, Cathepsin D, Cornified envelope, Epidermal differentiation, Involucrin, Loricrin, Filaggrin, Keratin, Sphingomyelinase, Transglutaminase




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