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J. Biol. Chem., Vol. 283, Issue 26, 18303-18313, June 27, 2008

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Pemphigus Vulgaris IgG-induced Desmoglein-3 Endocytosis and Desmosomal Disassembly Are Mediated by a Clathrin- and Dynamin-independent Mechanism^*

Emmanuella Delva, Jean Marie Jennings, Cathárine C. Calkins^¶, Margaret D. Kottke^¶, Victor Faundez, and Andrew P. Kowalczyk^¶1

From the Graduate Program in Biochemistry, Cell, and Developmental Biology, Department of Cell Biology, and ^¶Department of Dermatology, Emory University, Atlanta, Georgia 30332

Pemphigus vulgaris (PV) is a life-threatening autoimmune disease characterized by oral mucosal erosions and epidermal blistering. The autoantibodies generated target the desmosomal cadherin desmoglein-3 (Dsg3). Previous studies demonstrate that upon PV IgG binding, Dsg3 is internalized and enters an endo-lysosomal pathway where it is degraded. To define the endocytic machinery involved in PV IgG-induced Dsg3 internalization, human keratinocytes were incubated with PV IgG, and various tools were used to perturb distinct endocytic pathways. The PV IgG ·Dsg3 complex failed to colocalize with clathrin, and inhibitors of clathrin- and dynamin-dependent pathways had little or no effect on Dsg3 internalization. In contrast, cholesterol binding agents such as filipin and nystatin and the tyrosine kinase inhibitor genistein dramatically inhibited Dsg3 internalization. Furthermore, the Dsg3 cytoplasmic tail specified sensitivity to these inhibitors. Moreover, inhibition of Dsg3 endocytosis with genistein prevented disruption of desmosomes and loss of adhesion in the presence of PV IgG. Altogether, these results suggest that PV IgG-induced Dsg3 internalization is mediated through a clathrin- and dynamin-independent pathway and that Dsg3 endocytosis is tightly coupled to the pathogenic activity of PV IgG.

Received for publication, December 10, 2007 , and in revised form, April 18, 2008.

^* This work was supported, in whole or in part, by National Institutes of Health Grants R01 AR048266, R01 AR050501, R21AR50779 (to A. P. K.), F31 CA110278-02 (to E. D.), and T32 AR007587 (to M. D. K.). 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 Movies 1 and 2.

¹ To whom correspondence should be addressed: Dept. of Cell Biology, 615 Michael St., Rm. 465, Atlanta, GA 30322. Tel.: 404-727-8517; Fax: 404-727-6256; E-mail: akowalc{at}emory.edu.

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