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¹ Proteases and Tissue Remodeling Unit, National Institute of Dental and Craniofacial Research
² National Human Genome Research Institute, National Institutes of Health, Bethesda, MD 20892
³ Dows Institute, University of Iowa College of Dentistry, Iowa City, IA 52242
⁴ Department of Experimental Pathology, American Red Cross, Rockville, MD 20855
⁵ Department of Neuroscience, Weill Medical College of Cornell University and Burke Medical Research Institute, White Plains, NY 10605
⁶ Finsen Laboratory, DK-2100 Copenhagen, Denmark

Address correspondence to Thomas H. Bugge, Proteases and Tissue Remodeling Unit, Oral and Pharyngeal Cancer Branch, National Institute of Dental and Craniofacial Research, National Institutes of Health, 30 Convent Drive, Room 211, Bethesda, MD 20892. Tel.: (301) 435-1840. Fax: (301) 402-0823. email: thomas.bugge{at}nih.gov

Profilaggrin is a large epidermal polyprotein that is proteolytically processed during keratinocyte differentiation to release multiple filaggrin monomer units as well as a calcium-binding regulatory NH₂-terminal filaggrin S-100 protein. We show that epidermal deficiency of the transmembrane serine protease Matriptase/MT-SP1 perturbs lipid matrix formation, cornified envelope morphogenesis, and stratum corneum desquamation. Surprisingly, proteomic analysis of Matriptase/MT-SP1–deficient epidermis revealed the selective loss of both proteolytically processed filaggrin monomer units and the NH₂-terminal filaggrin S-100 regulatory protein. This was associated with a profound accumulation of profilaggrin and aberrant profilaggrin-processing products in the stratum corneum. The data identify keratinocyte Matriptase/MT-SP1 as an essential component of the profilaggrin-processing pathway and a key regulator of terminal epidermal differentiation.

Key Words: barrier function; lipid lamellar bodies; membrane serine protease; profilaggrin; stratum corneum

Abbreviations used in this paper: CE, cornified envelope; E, embryonic day.

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