Desmosome Disassembly in Response to Pemphigus Vulgaris IgG Occurs in Distinct Phases and can be Reversed by Expression of Exogenous Dsg3

• Type of Material: Article
• Authors: Jean Marie Jennings, Emory University; Dana K. Tucker, Emory University; Margaret D. Kottke, Emory University; Masataka Saito, Emory University; Emmanuella Delva, Emory University; Yasushi Hanakawa, Ehime University; Masayuki Amagai, Keio University; Andrew Kowalczyk, Emory University
• Language: English
• Date: 2011-03
• Publisher: Nature Publishing Group: Open Access Hybrid Model Option A
• Publication Version: Author Accepted Manuscript (After Peer Review)
• Copyright Statement: © 2011 The Society for Investigative Dermatology
• Final Published Version (URL): http://www.nature.com/jid/journal/v131/n3/full/jid2010389a.html
• Title of Journal or Parent Work: Journal of Investigative Dermatology
• ISSN: 0022-202X
• Volume: 131
• Issue: 3
• Start Page: 706
• End Page: 718
• Grant/Funding Information: This work was supported by funding from the NIH/NIAMS (R01 AR048266). MDK was supported by T32AR007587, DKT was supported by T32GM008367, and ED was supported by F31CA110278.
• Research Categories: Biology, Cell; Health Sciences, Medicine and Surgery

Abstract

Pemphigus vulgaris (PV) is an epidermal blistering disorder caused by antibodies directed against the desmosomal cadherin desmoglein-3 (Dsg3). The mechanism by which PV IgG disrupt adhesion is not fully understood. To address this issue, primary human keratinocytes and patient IgG were utilized to define the morphological, biochemical and functional changes triggered by PV IgG. Three phases of desmosome disassembly were distinguished. Analysis of fixed and living keratinocytes demonstrated that PV IgG cause rapid Dsg3 internalization which likely originates from a non-junctional pool of Dsg3. Subsequently, Dsg3 and other desmosomal components rearrange into linear arrays that run perpendicular to cell contacts. Dsg3 complexes localized at the cell surface are transported in a retrograde fashion along these arrays before being released into cytoplasmic vesicular compartments. These changes in Dsg3 distribution are followed by depletion of detergent insoluble Dsg3 pools and by the loss of cell adhesion strength. Importantly, this process of disassembly can be prevented by expressing exogenous Dsg3, thereby driving Dsg3 biosynthesis and desmosome assembly. These data support a model in which PV IgG cause the loss of cell adhesion by altering the dynamics of Dsg3 assembly into desmosomes and the turnover of cell surface pools of Dsg3 through endocytic pathways.