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Author Notes:

Correspondence: Andrew P. Kowalczyk; Email: akowalc@emory.edu

Authors' Contributions: Contributed equally: SS and MS

Conceived and designed the experiments: SS, MS and AK.

Performed the experiments: SS and MS.

Analyzed the data: SS, MS, VF, MK, AM and AK.

Contributed reagents/materials/analysis tools: VF and AM.

Wrote the paper: SS and AK.

Acknowledgments: We thank members of the Kowalczyk laboratory for insightful comments and advice with this study.

We also thank Xuming Mao and Aimee Payne (University of Pennsylvania) for their assistance with the human skin explant experiment.

Disclosures: The authors have declared that no competing interests exist.

Subjects:

Research Funding:

This work was supported by a grant (R01AR048266) from the National Institutes of Health.

Desmosome Assembly and Disassembly Are Membrane Raft-Dependent

Tools:

Journal Title:

PLoS ONE

Volume:

Volume 9, Number 1

Publisher:

, Pages e87809-e87809

Type of Work:

Article | Final Publisher PDF

Abstract:

Strong intercellular adhesion is critical for tissues that experience mechanical stress, such as the skin and heart. Desmosomes provide adhesive strength to tissues by anchoring desmosomal cadherins of neighboring cells to the intermediate filament cytoskeleton. Alterations in assembly and disassembly compromise desmosome function and may contribute to human diseases, such as the autoimmune skin blistering disease pemphigus vulgaris (PV). We previously demonstrated that PV auto-antibodies directed against the desmosomal cadherin desmoglein 3 (Dsg3) cause loss of adhesion by triggering membrane raft-mediated Dsg3 endocytosis. We hypothesized that raft membrane microdomains play a broader role in desmosome homeostasis by regulating the dynamics of desmosome assembly and disassembly. In human keratinocytes, Dsg3 is raft associated as determined by biochemical and super resolution immunofluorescence microscopy methods. Cholesterol depletion, which disrupts rafts, prevented desmosome assembly and adhesion, thus functionally linking rafts to desmosome formation. Interestingly, Dsg3 did not associate with rafts in cells lacking desmosomal proteins. Additionally, PV IgG-induced desmosome disassembly occurred by redistribution of Dsg3 into raft-containing endocytic membrane domains, resulting in cholesterol-dependent loss of adhesion. These findings demonstrate that membrane rafts are required for desmosome assembly and disassembly dynamics, suggesting therapeutic potential for raft targeting agents in desmosomal diseases such as PV.

Copyright information:

© 2014 Stahley et al.

This is an Open Access work distributed under the terms of the Creative Commons Attribution 4.0 International License (https://creativecommons.org/licenses/by/4.0/).
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