Home | Help | Feedback | Subscriptions | Archive | Search | Table of Contents

This Article Full Text Full Text (PDF, 705K) PPT slides of all figures Alert me when this article is cited Citation Map Services Email this article Similar articles in this journal Similar articles in PubMed Alert me to new content in the JCB Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via CrossRef Citing Articles via Google Scholar Google Scholar Articles by Caldelari, R. Articles by Müller, E. Search for Related Content PubMed PubMed Citation Articles by Caldelari, R. Articles by Müller, E. Related Collections Related Article Social Bookmarking                            What's this?

© The Rockefeller University Press, 0021-9525/2001//823 $5.00
The Journal of Cell Biology, Volume 153, Number 4, , 2001 823-834

A Central Role for the Armadillo Protein Plakoglobin in the Autoimmune Disease Pemphigus Vulgaris

^a Institute of Animal Pathology, University of Bern, CH-3012 Bern, Switzerland
^b Centre de Biologie du Developpement, 31062 Toulouse, France
Institute of Animal Pathology, Länggass-Strasse 122, 3012 Bern, Switzerland.41-31-631-26-3541-31-631-24-03 or 631-23-98

eliane.mueller{at}itpa.unibe.ch

In pemphigus vulgaris (PV), autoantibody binding to desmoglein (Dsg) 3 induces loss of intercellular adhesion in skin and mucous membranes. Two hypotheses are currently favored to explain the underlying molecular mechanisms: (a) disruption of adhesion through steric hindrance, and (b) interference of desmosomal cadherin-bound antibody with intracellular events, which we speculated to involve plakoglobin. To investigate the second hypothesis we established keratinocyte cultures from plakoglobin knockout (PG^–/–) embryos and PG^+/+ control mice. Although both cell types exhibited desmosomal cadherin-mediated adhesion during calcium-induced differentiation and bound PV immunoglobin (IgG) at their cell surface, only PG^+/+ keratinocytes responded with keratin retraction and loss of adhesion. When full-length plakoglobin was reintroduced into PG^–/– cells, responsiveness to PV IgG was restored. Moreover, in these cells like in PG^+/+ keratinocytes, PV IgG binding severely affected the linear distribution of plakoglobin at the plasma membrane. Taken together, the establishment of an in vitro model using PG^+/+ and PG^–/– keratinocytes allowed us (a) to exclude the steric hindrance only hypothesis, and (b) to demonstrate for the first time that plakoglobin plays a central role in PV, a finding that will provide a novel direction for investigations of the molecular mechanisms leading to PV, and on the function of plakoglobin in differentiating keratinocytes.

Key Words: catenins • desmosomes • mouse keratinocytes • epithelial differentiation • blistering disease

© 2001 The Rockefeller University Press

Abbreviations used in this paper: Dsg, desmoglein; E-cad, E-cadherin; GFP, green fluorescent protein; IF, immunofluorescence; nhIgG, normal human IgG; PV, pemphigus vulgaris; WB, Western blot.

CiteULike

Complore

Connotea

Del.icio.us

Digg

Facebook

Reddit

Technorati

Twitter

This article has been cited by other articles:

• Delva, E., Tucker, D. K., Kowalczyk, A. P. (2009). The Desmosome. Cold Spring Harb. Perspect. Biol. 1: a002543-a002543 [Abstract] [Full Text]  
• Lee, H. E., Berkowitz, P., Jolly, P. S., Diaz, L. A., Chua, M. P., Rubenstein, D. S. (2009). Biphasic Activation of p38MAPK Suggests That Apoptosis Is a Downstream Event in Pemphigus Acantholysis. J. Biol. Chem. 284: 12524-12532 [Abstract] [Full Text]  
• Heupel, W.-M., Muller, T., Efthymiadis, A., Schmidt, E., Drenckhahn, D., Waschke, J. (2009). Peptides Targeting the Desmoglein 3 Adhesive Interface Prevent Autoantibody-induced Acantholysis in Pemphigus. J. Biol. Chem. 284: 8589-8595 [Abstract] [Full Text]  
• Heupel, W.-M., Engerer, P., Schmidt, E., Waschke, J. (2009). Pemphigus Vulgaris IgG Cause Loss of Desmoglein-Mediated Adhesion and Keratinocyte Dissociation Independent of Epidermal Growth Factor Receptor. Am. J. Pathol. 174: 475-485 [Abstract] [Full Text]  
• Li, N., Zhao, M., Wang, J., Liu, Z., Diaz, L. A. (2009). Involvement of the Apoptotic Mechanism in Pemphigus Foliaceus Autoimmune Injury of the Skin. J. Immunol. 182: 711-717 [Abstract] [Full Text]  
• Schmidt, E., Gutberlet, J., Siegmund, D., Berg, D., Wajant, H., Waschke, J. (2009). Apoptosis is not required for acantholysis in pemphigus vulgaris. Am. J. Physiol. Cell Physiol. 296: C162-C172 [Abstract] [Full Text]  
• Heupel, W.-M., Zillikens, D., Drenckhahn, D., Waschke, J. (2008). Pemphigus Vulgaris IgG Directly Inhibit Desmoglein 3-Mediated Transinteraction. J. Immunol. 181: 1825-1834 [Abstract] [Full Text]  
• Lanza, A., Cirillo, N., Rossiello, R., Rienzo, M., Cutillo, L., Casamassimi, A., de Nigris, F., Schiano, C., Rossiello, L., Femiano, F., Gombos, F., Napoli, C. (2008). Evidence of Key Role of Cdk2 Overexpression in Pemphigus Vulgaris. J. Biol. Chem. 283: 8736-8745 [Abstract] [Full Text]  
• Spindler, V., Drenckhahn, D., Zillikens, D., Waschke, J. (2007). Pemphigus IgG Causes Skin Splitting in the Presence of Both Desmoglein 1 and Desmoglein 3. Am. J. Pathol. 171: 906-916 [Abstract] [Full Text]  
• Yamamoto, Y., Aoyama, Y., Shu, E., Tsunoda, K., Amagai, M., Kitajima, Y. (2007). Anti-desmoglein 3 (Dsg3) Monoclonal Antibodies Deplete Desmosomes of Dsg3 and Differ in Their Dsg3-depleting Activities Related to Pathogenicity. J. Biol. Chem. 282: 17866-17876 [Abstract] [Full Text]  
• Waschke, J., Spindler, V., Bruggeman, P., Zillikens, D., Schmidt, G., Drenckhahn, D. (2006). Inhibition of Rho A activity causes pemphigus skin blistering. JCB 175: 721-727 [Abstract] [Full Text]  
• Stanley, J. R., Amagai, M. (2006). Pemphigus, Bullous Impetigo, and the Staphylococcal Scalded-Skin Syndrome. NEJM 355: 1800-1810 [Full Text]  
• Berkowitz, P., Hu, P., Warren, S., Liu, Z., Diaz, L. A., Rubenstein, D. S. (2006). p38MAPK inhibition prevents disease in pemphigus vulgaris mice. Proc. Natl. Acad. Sci. USA 103: 12855-12860 [Abstract] [Full Text]  
• Calkins, C. C., Setzer, S. V., Jennings, J. M., Summers, S., Tsunoda, K., Amagai, M., Kowalczyk, A. P. (2006). Desmoglein Endocytosis and Desmosome Disassembly Are Coordinated Responses to Pemphigus Autoantibodies. J. Biol. Chem. 281: 7623-7634 [Abstract] [Full Text]  
• Kottke, M. D., Delva, E., Kowalczyk, A. P. (2006). The desmosome: cell science lessons from human diseases.. J. Cell Sci. 119: 797-806 [Abstract] [Full Text]  
• Yin, T., Getsios, S., Caldelari, R., Godsel, L. M., Kowalczyk, A. P., Muller, E. J., Green, K. J. (2005). Mechanisms of Plakoglobin-dependent Adhesion: DESMOSOME-SPECIFIC FUNCTIONS IN ASSEMBLY AND REGULATION BY EPIDERMAL GROWTH FACTOR RECEPTOR. J. Biol. Chem. 280: 40355-40363 [Abstract] [Full Text]  
• Berkowitz, P., Hu, P., Liu, Z., Diaz, L. A., Enghild, J. J., Chua, M. P., Rubenstein, D. S. (2005). Desmosome Signaling: INHIBITION OF p38MAPK PREVENTS PEMPHIGUS VULGARIS IgG-INDUCED CYTOSKELETON REORGANIZATION. J. Biol. Chem. 280: 23778-23784 [Abstract] [Full Text]  
• Yin, T., Getsios, S., Caldelari, R., Kowalczyk, A. P., Muller, E. J., Jones, J. C. R., Green, K. J. (2005). Plakoglobin suppresses keratinocyte motility through both cell-cell adhesion-dependent and -independent mechanisms. Proc. Natl. Acad. Sci. USA 102: 5420-5425 [Abstract] [Full Text]  
• Nguyen, V. T., Arredondo, J., Chernyavsky, A. I., Pittelkow, M. R., Kitajima, Y., Grando, S. A. (2004). Pemphigus Vulgaris Acantholysis Ameliorated by Cholinergic Agonists. Arch Dermatol 140: 327-334 [Abstract] [Full Text]  
• Tsunoda, K., Ota, T., Aoki, M., Yamada, T., Nagai, T., Nakagawa, T., Koyasu, S., Nishikawa, T., Amagai, M. (2003). Induction of Pemphigus Phenotype by a Mouse Monoclonal Antibody Against the Amino-Terminal Adhesive Interface of Desmoglein 3. J. Immunol. 170: 2170-2178 [Abstract] [Full Text]  
• Kofron, M., Heasman, J., Lang, S. A., Wylie, C. C. (2002). Plakoglobin is required for maintenance of the cortical actin skeleton in early Xenopus embryos and for cdc42-mediated wound healing. JCB 158: 695-708 [Abstract] [Full Text]  
• Posthaus, H., Williamson, L., Baumann, D., Kemler, R., Caldelari, R., Suter, M. M., Schwarz, H., Muller, E. (2002). {beta}-Catenin is not required for proliferation and differentiation of epidermal mouse keratinocytes. J. Cell Sci. 115: 4587-4595 [Abstract] [Full Text]  

Home | Help | Feedback | Subscriptions | Archive | Search | Table of Contents