demecolcine and Arrhythmogenic-Right-Ventricular-Dysplasia

Mechanisms by which microtubule plus ends interact with regions of cell-cell contact during tissue development and morphogenesis are not fully understood. We characterize a previously unreported interaction between the microtubule binding protein end-binding 1 (EB1) and the desmosomal protein desmoplakin (DP), and demonstrate that DP-EB1 interactions enable DP to modify microtubule organization and dynamics near sites of cell-cell contact. EB1 interacts with a region of the DP N terminus containing a hotspot for pathogenic mutations associated with arrhythmogenic cardiomyopathy (AC). We show that a subset of AC mutations, in addition to a mutation associated with skin fragility/woolly hair syndrome, impair gap junction localization and function by misregulating DP-EB1 interactions and altering microtubule dynamics. This work identifies a novel function for a desmosomal protein in regulating microtubules that affect membrane targeting of gap junction components, and elucidates a mechanism by which DP mutations may contribute to the development of cardiac and cutaneous diseases.

Topics: Animals; Arrhythmogenic Right Ventricular Dysplasia; Cell Communication; Cell Line; Chlorocebus aethiops; Connexin 43; COS Cells; Demecolcine; Desmoglein 2; Desmoplakins; Desmosomes; Gap Junctions; HEK293 Cells; Humans; Microtubule-Associated Proteins; Microtubules; Morphogenesis; Mutation; Rats; Rats, Sprague-Dawley; RNA Interference; RNA, Small Interfering; Tubulin Modulators