Gap junctions mediate intercellular communication and thus have important roles in maintaining tissue integrity; they are formed by members of the connexin family of channel-forming proteins. Connexin 43 (Cx43) is the most abundant connexin in humans and is frequently aberrantly regulated at the post-translational level in cancer, resulting in loss of gap junctions. The oncogenic E3 ubiquitin ligase neural precursor cell-expressed developmentally downregulated gene 4 (NEDD4) has been shown to interact with Cx43 and mediates its degradation by autophagy upon serum starvation, but its role in regulating Cx43 levels under basal conditions remains unclear. To gain a better understanding of how NEDD4 regulates gap junctions, Edward Leithe and colleagues now (p. 2867) address the effect of NEDD4 on Cx43 in human carcinoma cells. The authors find that overexpression of NEDD4 in HeLa and C33A cells results in a near complete loss of gap junctions, owing to increased Cx43 ubiquitylation and its lysosomal degradation. As shown here, this depends on the HECT domain of NEDD4. Furthermore, the authors demonstrate that NEDD4 regulates Cx43 levels both under basal conditions and in response to activation of protein kinase C (PKC). This study thus presents the first evidence for an oncogenic E3 ligase to induce gap junction loss in cancer cells; this might be of relevance for future therapeutic applications as oncogenic ubiquitin ligases constitute possible cancer targets.