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The C-terminal unique region of desmoglein 2 inhibits its internalization via tail–tail interactions

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posted on 06.12.2013, 00:00 by Jing Chen, Oxana E. Nekrasova, Dipal M. Patel, Jodi L. Klessner, Lisa M. Godsel, Jennifer L. Koetsier, Evangeline V. Amargo, Bhushan V. Desai, Kathleen J. Green
Desmosomal cadherins, desmogleins (Dsgs) and desmocollins, make up the adhesive core of intercellular junctions called desmosomes. A critical determinant of epithelial adhesive strength is the level and organization of desmosomal cadherins on the cell surface. The Dsg subclass of desmosomal cadherins contains a C-terminal unique region (Dsg unique region [DUR]) with unknown function. In this paper, we show that the DUR of Dsg2 stabilized Dsg2 at the cell surface by inhibiting its internalization and promoted strong intercellular adhesion. DUR also facilitated Dsg tail-tail interactions. Forced dimerization of a Dsg2 tail lacking the DUR led to decreased internalization, supporting the conclusion that these two functions of the DUR are mechanistically linked. We also show that a Dsg2 mutant, V977fsX1006, identified in arrhythmogenic right ventricular cardiomyopathy patients, led to a loss of Dsg2 tail self-association and underwent rapid endocytosis in cardiac muscle cells. Our observations illustrate a new mechanism desmosomal cadherins use to control their surface levels, a key factor in determining their adhesion and signaling roles.

Funding

This work was supported by National Institutes of Health grants CA122151 and AR041836 and a Transatlantic Network of Excellence grant from the Leducq Foundation as well as the J.L. Mayberry Endowment to K.J. Green.

History

Publisher Statement

© 2012 Chen et al. This article is distributed under the terms of an Attribution–Noncommercial– Share Alike–No Mirror Sites license for the first six months after the publication date (see http://www.rupress.org/terms). After six months it is available under a Creative Commons License (Attribution–Noncommercial–Share Alike 3.0 Unported license, as described at http://creativecommons.org/licenses/by-nc-sa/3.0/). © 2012 by Rockefeller University Press, Journal of Cell Biology.

Publisher

Rockefeller University Press

Language

en_US

issn

0021-9525

Issue date

05/11/2012

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