Abstract
Gap junctions (GJ) are specialized cell-cell contacts formed by connexins (Cxs), which provide direct communication between adjacent cells. Cx43 ubiquitination has been suggested to induce the internalization of GJs, as well as the recruitment of the autophagy receptor p62 to mediate binding to LC3B and degradation by macroautophagy. In this report, we describe a functional LC3 interacting region (LIR), present in the amino terminal of most Cx protein family members, which can mediate the autophagy degradation of Cx43 without the need of ubiquitin. Mutation of the LIR motif on Cx37, Cx43, Cx46 and Cx50 impairs interaction with LC3B and GABARAP without compromising protein ubiquitination. Through in vitro protein-protein interaction assays, we demonstrate that this LIR motif is required for the binding of Cx43 to LC3B and GABARAP. Overall, our findings describe an alternative mechanism whereby Cxs interact with LC3/GABARAP proteins, envisioning a new model for the autophagy degradation of connexins.
Highlights
Connexins (Cx) are a family of proteins that directly connect the cytoplasm of adjacent cells through the formation of gap junction (GJ) channels
Previous studies demonstrated that connexin proteins are degraded by autophagy
We and others have reported that degradation of Cx43 by macroautophagy requires prior ubiquitination of Cx43 and its further recognition by p62 [10,11]
Summary
Connexins (Cx) are a family of proteins that directly connect the cytoplasm of adjacent cells through the formation of gap junction (GJ) channels. Twenty members form the connexin family, while at least seventeen members have been reported in rats. Each connexin consists of four transmembrane regions, two extracellular loops and one intracellular loop, with both the amino and carboxyl terminals facing the cytosol. Connexin proteins oligomerize into hexameric structures termed hemichannels and are transported to the plasma membrane, where they may dock to hemichannels from adjacent cells to form a functional GJ channel. The carboxyl terminal is where most differences between connexins are found, and a large part of the protein interactions and post-translational modifications of connexins are thought to occur in this region [2].
Sign-in/Register to view highlights & summary Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
