Human Molecular Genetics Advance Access originally published online on March 25, 2004
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Human Molecular Genetics, 2004, Vol. 13, No. 10 1069-1079
DOI: 10.1093/hmg/ddh115
Human Molecular Genetics, Vol. 13, No. 10 © Oxford University Press 2004; all rights reserved
Evidence that unrestricted legumain activity is involved in disturbed epidermal cornification in cystatin M/E deficient mice
1Department of Dermatology, Nijmegen Center for Molecular Life Sciences, University Medical Center Nijmegen, PO Box 9101, 6500 HB Nijmegen, The Netherlands, 2Department of Pharmacology, School of Pharmacy, Oslo, Norway, 3Department of Applied Molecular Bioscience, Graduate School of Bioagricultural Sciences, Nagoya University, Nagoya, Japan, 4Department of Botany, Graduate School of Science, Kyoto University, Kyoto, Japan, 5School of Chemistry and Biochemistry, Georgia Institute of Technology, Atlanta, Georgia, USA and 6Department of Microbiology, Faculty of Science, University of Nijmegen, The Netherlands
Received January 28, 2004; Accepted March 11, 2004
Homozygosity for Cst6 null alleles causes the phenotype of the ichq mouse, which is a model for human harlequin ichthyosis (OMIM 242500), a genetically heterogeneous group of keratinization disorders. Here we report evidence for the mechanism by which deficiency of the cysteine protease inhibitor cystatin M/E (the Cst6 gene product) leads to disturbed cornification, impaired barrier function and dehydration. Absence of cystatin M/E causes unrestricted activity of its target protease legumain in hair follicles and epidermis, which is the exact location where cystatin M/E is normally expressed. Analysis of stratum corneum proteins revealed a strong decrease of soluble loricrin monomers in skin extracts of ichq mice, although normal levels of loricrin were present in the stratum granulosum and stratum corneum of ichq mice, as shown by immunohistochemistry. This suggested a premature or enhanced crosslinking of loricrin monomers in ichq mice by transglutaminase 3 (TGase 3). In these mice, we indeed found strongly increased levels of TGase 3 that was processed into its activated 30 and 47 kDa subunits, compared to wild-type mice. This study shows that cystatin M/E and legumain form a functional dyad in epidermis in vivo. Disturbance of this protease–antiprotease balance causes increased enzyme activity of TGase 3 that could explain the observed abnormal cornification.
* To whom correspondence should be addressed. Tel: +31 243617245; Fax: +31 243541184; Email: p.zeeuwen{at}derma.umcn.nl
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