Arrhythmogenic cardiomyopathy-associated mutations in desmoplakin impair gap junction localization and function by misregulating DP-EB1 interactions and altering microtubule dynamics.
How do pathogenic mutations in desmoplakin associated with arrhythmogenic cardiomyopathy affect microtubule dynamics and gap junction localization?
Identifies a novel mechanism where desmoplakin mutations associated with arrhythmogenic cardiomyopathy disrupt microtubule dynamics and gap junction targeting via impaired EB1 interactions.
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.
Patel et al. (Mon,) conducted a other in Arrhythmogenic cardiomyopathy. Desmoplakin (DP) mutations vs. Wild-type DP was evaluated on Gap junction localization and function, and microtubule dynamics. Arrhythmogenic cardiomyopathy-associated mutations in desmoplakin impair gap junction localization and function by misregulating DP-EB1 interactions and altering microtubule dynamics.