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J. Biol. Chem., Vol. 281, Issue 9, 5406-5415, March 3, 2006

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Cathepsin D Is Present in Human Eccrine Sweat and Involved in the Postsecretory Processing of the Antimicrobial Peptide DCD-1L^*

Daniel Baechle, Thomas Flad, Alexander Cansier, Heiko Steffen^¶, Birgit Schittek^¶, Jonathan Tolson, Timo Herrmann, Hassan Dihazi^||, Alexander Beck^**, Gerhard A. Mueller^||, Margret Mueller, Stefan Stevanovic, Claus Garbe^¶, Claudia A. Mueller, and Hubert Kalbacher¹

From the Medical and Natural Sciences Research Center, University of Tübingen, 72074 Tübingen, Germany, the Section for Transplantation Immunology and Immunohematology, University of Tübingen, 72072 Tübingen, Germany, the Departments of ^¶Dermatology and Immunology, University of Tübingen, 72076 Tübingen, Germany, the ^||Department of Nephrology and Rheumatology, University Hospital Göttingen, 37075 Göttingen, Germany, and the ^**Department of Internal Medicine IV, Division of Clinical Chemistry, University Hospital Tübingen, 72076 Tübingen, Germany

The protein pattern of healthy human eccrine sweat was investigated and 10 major proteins were detected from which apolipoprotein D, lipophilin B, and cathepsin D (CatD) were identified for the first time in human eccrine sweat. We focused our studies on the function of the aspartate protease CatD in sweat. In vitro digestion experiments using a specific fluorescent CatD substrate showed that CatD is enzymatically active in human sweat. To identify potential substrates of CatD in human eccrine sweat LL-37 and DCD-1L, two antimicrobial peptides present in sweat, were digested in vitro with purified CatD. LL-37 was not significantly digested by CatD, whereas DCD-1L was cleaved between Leu⁴⁴ and Asp⁴⁵ and between Leu²⁹ and Glu³⁰ almost completely. The DCD-1L-derived peptides generated in vitro by CatD were also found in vivo in human sweat as determined by surface-enhanced laser desorption/ionization (SELDI) mass spectrometry. Furthermore, besides the CatD-processed peptides we identified additionally DCD-1L-derived peptides that are generated upon cleavage with a 1,10-phenanthroline-sensitive carboxypeptidase and an endoprotease. Taken together, proteolytic processing generates 12 DCD-1L-derived peptides. To elucidate the functional significance of postsecretory processing the antimicrobial activity of three CatD-processed DCD-1L peptides was tested. Whereas two of these peptides showed no activity against Gram-positive and Gram-negative bacteria, one DCD-1L-derived peptide showed an even higher activity against Escherichia coli than DCD-1L. Functional analysis indicated that proteolytic processing of DCD-1L by CatD in human sweat modulates the innate immune defense of human skin.

Received for publication, April 28, 2005 , and in revised form, November 22, 2005.

^* This work was supported by Deutsche Forschungsgemeinschaft Grants SFB 510 and SCHI 510/3-1 and Bundesministerium für Bildung und Forschung Grant BMBF FKZ 0312879. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ To whom correspondence should be addressed: Ob dem Himmelreich 7, 72074 Tübingen, Germany. Tel.: 49-7071-2985212; Fax: 49-7071-294507; E-mail: kalbacher{at}uni-tuebingen.de.

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