Fig. 4

Connexin degradation by autophagy pathway: a Nedd4 mediates ubiquitination of Cx43 (shown Cx43 subunit) in gap junction plaques and recruits Eps15 to gap junctions upon nutrient starvation. Eps15 can interact with Cx43 via ubiquitin-binding domain, thereby promoting its internalization. Upon starvation, Cx43-p62-LC3 interaction can direct Cx43 for autophagy degradation. b In normal conditions, autophagosome precursor proteins such as PI3K complex (Beclin 1, Vps34 and Vps15) and Atg16 are associated with Cx43 (as Cx-Atg complex) at the plasma membrane. The Cx-Atg complex negatively regulates autophagy. During starvation, the arrival of Atg14 and Atg9 to the Cx43-enriched plasma membrane, activates Vps34 kinase, thereby inducing internalization of the Cx-Atg complex and the delivery of these pre-autophagosomal components to the sites of autophagosome formation. Internalization of Cx43 requires the presence of Eps15 (not shown). For clarity reasons, the internalization of only one Cx43 subunit is shown in both channels