Desmosome assembly and disassembly are membrane raft-dependent.
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.
Department of Cell Biology, Emory University School of Medicine, Atlanta, Georgia, United States of America ; Graduate Program in Biochemistry, Cell and Developmental Biology, Emory University School of Medicine, Atlanta, Georgia, United States of America.
Sara N
SN
Stahley
Department of Cell Biology, Emory University School of Medicine, Atlanta, Georgia, United States of America.
Masataka
M
Saito
Department of Cell Biology, Emory University School of Medicine, Atlanta, Georgia, United States of America.
Victor
V
Faundez
Department of Cell Biology, Emory University School of Medicine, Atlanta, Georgia, United States of America ; Division of Pulmonary, Allergy and Critical Care Medicine, Emory University School of Medicine, Atlanta, Georgia, United States of America.
Michael
M
Koval
Department of Cell Biology, Emory University School of Medicine, Atlanta, Georgia, United States of America.
Alexa L
AL
Mattheyses
Department of Cell Biology, Emory University School of Medicine, Atlanta, Georgia, United States of America ; Department of Dermatology, Emory University School of Medicine, Atlanta, Georgia, United States of America ; Winship Cancer Institute, Emory University School of Medicine, Atlanta, Georgia, United States of America.
Andrew P
AP
Kowalczyk
D002448:Cell Adhesion / Q000502:physiology; D002462:Cell Membrane / Q000378:metabolism*; D002478:Cells, Cultured; D002784:Cholesterol / Q000378:metabolism; D051184:Desmoglein 3 / Q000378:metabolism*; D004705:Endocytosis / Q000502:physiology; D006801:Humans; D007074:Immunoglobulin G / Q000378:metabolism; D015603:Keratinocytes / Q000378:metabolism; D016253:Microscopy, Immunoelectron / Q000379:methods; D010392:Pemphigus / Q000378:metabolism
C071894:DSG3 protein, human; D051184:Desmoglein 3; D007074:Immunoglobulin G; D002784:Cholesterol