CYLD deubiquitinates plakoglobin to promote Cx43 membrane targeting and gap junction assembly in the heart

Abstract

During heart maturation, gap junctions assemble into hemichannels and polarize to the intercalated disc at cell borders to mediate electrical impulse conduction. However, the molecular mechanism underpinning cardiac gap junction assembly remains elusive. Herein, we demonstrate an important role for the deubiquitinating enzyme cylindromatosis (CYLD) in this process. Depletion of CYLD in mice impairs the formation of cardiac gap junctions, accelerates cardiac fibrosis, and increases heart failure. Mechanistically, CYLD interacts with plakoglobin and removes lysine 63-linked polyubiquitin chains from plakoglobin. The deubiquitination ofplakoglobin enhances its interaction with the desmoplakin/end-binding protein 1 complex localized atthe microtubule plus end, thereby promoting microtubule-dependent transport of connexin 43 (Cx43), akey component of gap junctions, to the cell membrane. These findings establish CYLD as a critical playerin regulating gap junction assembly and have important implications in heart development and diseases.