J. Biochem, 2003, Vol. 133, No. 2 197-206
© 2003 Japanese Biochemical Society
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Extracellular Cleavage of Bullous Pemphigoid Antigen 180/Type XVII Collagen and Its Involvement in Hemidesmosomal Disassembly
1 Department of Dermatology, University of Würzburg, Würzburg 97080, Germany; 2 Nippon Organon, Osaka 534-0016; and 3 Unit of Biosystems, Graduate School of Human Informatics, Nagoya University, Nagoya 464-8601
Bullous pemphigoid antigen 180 (BP180)/type XVII collagen is a transmembrane hemidesmosomal protein. Previously, we demonstrated that the collagenous ectodomain of BP180 can be cleaved within the extracellular non-collagenous (NC) 16A domain adjacent to the cell membrane and released from the cell surface. Here, we report that the BP180 cleavage is mediated by a membrane-associated metalloprotease expressed in epithelial cells. A tissue inhibitor of metalloprotease 1 (TIMP-1), but not TIMP-2, like the synthetic metalloprotease inhibitor KB-R8301, significantly reduced the cleavage. Within epithelial cells cultured for more than 36 h past confluency, antibodies to BP180 showed a reduced hemidesmosomal staining. Observed for the first time, addition of KB-R8301 to the cell culture preserved this staining. To examine the effect of the extracellular cleavage of BP180 on molecular interactions among hemidesmosomal components, we eliminated its collagenous extracellular portion, except for the NC16A domain, by collagenase digestion. Interestingly, this collagenase treatment caused partial disassembly of hemidesmosomal components in cultured human keratinocytes. Moreover, a monoclonal antibody specific for the cleaved extracellular fragment detected a unique tissue distribution of the fragment that might reflect an association of the cleavage process with the mitotic activity of epithelial tissues. Our observations demonstrate that the cleavage of BP180 occurring within the NC16A domain is mediated by a membrane-associated metalloprotease and suggest a possible involvement of the cleavage in hemidesmosomal disassembly.
+ To whom correspondence should be addressed. Tel: +49-931-201-26753, Fax: +49-931-201-26357, E-mail: Hirako_Y{at}klinik.uni-wuerzburg.de
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