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J. Biol. Chem., Vol. 280, Issue 25, 23778-23784, June 24, 2005

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Desmosome Signaling

INHIBITION OF p38MAPK PREVENTS PEMPHIGUS VULGARIS IgG-INDUCED CYTOSKELETON REORGANIZATION^*

Paula Berkowitz, Peiqi Hu, Zhi Liu, Luis A. Diaz, Jan J. Enghild, Michael P. Chua¶, and David S. Rubenstein||**

From the Departments of Dermatology and ^¶Cell and Molecular Physiology and the ^||Lineberger Comprehensive Cancer Center University of North Carolina-Chapel Hill School of Medicine, Chapel Hill, North Carolina 27599 and the Department of Molecular Biology, University of Aarhus, DK-8000 Århus, Denmark

In the human autoimmune blistering disease pemphigus vulgaris (PV) pathogenic antibodies bind the desmosomal cadherin desmoglein-3 (dsg3), causing epidermal cell-cell detachment (acantholysis). Pathogenic PV dsg3 autoantibodies were used to initiate desmosome signaling in human keratinocyte cell cultures. Heat shock protein 27 (HSP27) and p38MAPK were identified as proteins rapidly phosphorylated in response to PV IgG. Inhibition of p38MAPK activity prevented PV IgG-induced HSP27 phosphorylation, keratin filament retraction, and actin reorganization. These observations suggest that PV IgG binding to dsg3 activates desmosomal signal transduction cascades leading to (i) p38MAPK and HSP27 phosphorylation and (ii) cytoskeletal reorganization, supporting a mechanistic role for signaling in PV IgG-induced acantholysis. Targeting desmosome signaling via inhibition of p38MAPK and HSP27 phosphorylation may provide novel treatments for PV and other desmosome-associated blistering diseases.

Received for publication, February 4, 2005 , and in revised form, April 13, 2005.

^* This work was supported by National Institutes of Health Grants RO1 AI49427-01 (to D. S. R.) and RO1 AR30281, RO1AR32599, and T32 AR07369 (to L. A. D.). 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.

^** To whom correspondence should be addressed: Dept. of Dermatology, University of North Carolina-Chapel Hill School of Medicine, Suite 3100 Thurston-Bowles Bldg. CB 7287, Chapel Hill, NC 27599-7287. Tel.: 919-843-7092; Fax: 919-966-3898; E-mail: druben{at}med.unc.edu.

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