Model of Dsg2 internalization. DUR inhibits Dsg2 internalization by promoting Dsg2 tail–tail interaction. DUR mediates Dsg2 tail–tail interaction, which stabilizes Dsg2 at the cell surface by inhibiting its internalization. When DUR–DUR interaction is disrupted (e.g., by mutation or deletion of the DUR), Dsg2 is more rapidly internalized from the cell surface. Dsg2 undergoes cholesterol- and dynamin-dependent endocytosis, independent of the status of DUR.