title: Disease mutations in desmoplakin inhibit Cx43 membrane targeting mediated by desmoplakin-EB1 interactions.
abstract: 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.
authors.affiliation: Department of Pathology and Department of Dermatology, Northwestern University Feinberg School of Medicine, Chicago, IL 60611.
authors.forename: Dipal M
authors.initials: DM
authors.lastname: Patel
authors.affiliation: Department of Pathology and Department of Dermatology, Northwestern University Feinberg School of Medicine, Chicago, IL 60611.
authors.forename: Adi D
authors.initials: AD
authors.lastname: Dubash
authors.affiliation: Department of Cell and Developmental Biology, Weill Cornell Medical College of Cornell University, New York, NY 10065.
authors.forename: Geri
authors.initials: G
authors.lastname: Kreitzer
authors.affiliation: Department of Pathology and Department of Dermatology, Northwestern University Feinberg School of Medicine, Chicago, IL 60611 Department of Pathology and Department of Dermatology, Northwestern University Feinberg School of Medicine, Chicago, IL 60611 kgreen@northwestern.edu.
authors.forename: Kathleen J
authors.initials: KJ
authors.lastname: Green
mesh_terms: D000818:Animals; D019571:Arrhythmogenic Right Ventricular Dysplasia / Q000235:genetics*; D019556:COS Cells; D002450:Cell Communication; D002460:Cell Line; D002522:Chlorocebus aethiops; D018031:Connexin 43 / Q000378:metabolism*; D003703:Demecolcine / Q000494:pharmacology; D051301:Desmoglein 2 / Q000235:genetics; D051180:Desmoplakins / Q000235:genetics / Q000378:metabolism*; D003896:Desmosomes / Q000502:physiology; D017629:Gap Junctions / Q000235:genetics / Q000473:pathology; D057809:HEK293 Cells; D006801:Humans; D008869:Microtubule-Associated Proteins / Q000378:metabolism*; D008870:Microtubules / Q000378:metabolism*; D009024:Morphogenesis; D009154:Mutation; D034622:RNA Interference; D034741:RNA, Small Interfering; D051381:Rats; D017207:Rats, Sprague-Dawley; D050257:Tubulin Modulators / Q000494:pharmacology
chemical_list: D018031:Connexin 43; C495314:DSG2 protein, human; D051301:Desmoglein 2; D051180:Desmoplakins; C500985:MAPRE1 protein, human; D008869:Microtubule-Associated Proteins; D034741:RNA, Small Interfering; D050257:Tubulin Modulators; D003703:Demecolcine