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J. Biol. Chem., Vol. 280, Issue 40, 34019-34024, October 7, 2005

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Shedding of Collagen XVII Ectodomain Depends on Plasma Membrane Microenvironment^*

From the Department of Dermatology, University of Freiburg, 79104 Freiburg, Germany

Collagen XVII, a hemidesmosomal component, mediates the adhesion of epidermal keratinocytes to the underlying basement membrane. It exists as a full-length transmembrane protein and a soluble ectodomain that is proteolytically released from the cell surface by sheddases of a disintegrin and metalloproteinase (ADAM) family; TACE, the tumor necrosis factor--converting enzyme, is the major physiological proteinase. Because both collagen XVII and the ADAMs are transmembrane proteins, their plasma membrane microenvironment can influence shedding. Lipid rafts, assemblies of sphingolipids and cholesterol within the plasma membrane, are responsible for the separation of membrane proteins and are thought to regulate shedding of cell surface proteins. In this study we analyzed the influence of the cholesterol-depleting agent methyl--cyclodextrin (MCD), which disintegrates lipid rafts, on the shedding of collagen XVII in HaCaT keratinocytes and in transfected COS-7 cells. Increasing concentrations of MCD led to a dose-dependent decrease of membrane cholesterol levels and to stimulation of collagen XVII shedding. The stimulation was completely inhibited by sheddase inhibitors, and experiments with COS-7 cells co-transfected with TACE and collagen XVII demonstrated that TACE mediated the low cholesterol-dependent shedding. Co-patching analysis by double immunofluorescence staining revealed co-localization of collagen XVII with the raft resident phosphatidylinositol-linked placental alkaline phosphatase and segregation from the non-raft protein human transferrin receptor, indicating that a majority of collagen XVII molecules was incorporated into lipid rafts. These data deliver the first evidence for the role of plasma membrane lipid organization in the regulation of collagen XVII shedding and, therefore, in the regulation of keratinocyte migration and differentiation.

Received for publication, April 6, 2005 , and in revised form, June 22, 2005.

^* This work was supported by German Research Council (DFG) Grants SFB 620-C5 and BR1475/6-3 (to L. B.-T.), a grant from the German Federal Ministry for Education and Research (BMBF) (Network Epidermolysis bullosa), and European Union Contract QLG1-CT-2001-02007. 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.

The on-line version of this article (available at http://www.jbc.org) contains supplemental data in the form of Fig. 1 showing collagen XVII co-patching with PLAP and segregation of HTrR after antibody cross-linking.

¹ To whom correspondence may be addressed: Dept. of Dermatology, University of Freiburg, Hauptstr. 7, 79104 Freiburg, Germany. Tel.: 49-761-270-6721; Fax: 49-761-270-6720; E-mail: zimina{at}haut.ukl.uni-freiburg.de or claus_franzke{at}haut.ukl.uni-freiburg.de.

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