MGRN 1‐dependent pigment‐type switching requires its ubiquitination activity but not its interaction with TSG 101 or NEDD 4

Mice lacking the E3 ubiquitin ligase mahogunin ring finger‐1 ( MGRN 1) have a pleiotropic phenotype that includes spongiform neurodegeneration, embryonic patterning defects, and dark fur due to a defect in pigment‐type switching. The only MGRN 1 ubiquitination target identified to date is tumor susceptibility gene 101 ( TSG 101), a component of the endosomal trafficking machinery. Here, we show that MGRN 1 also interacts with but does not ubiquitinate NEDD 4, a HECT ‐domain ubiquitin ligase involved in endosomal trafficking. Using transgenesis in mice, we demonstrate that pigment‐type switching likely requires MGRN 1′s ubiquitin ligase activity but not its ability to bind TSG 101 or NEDD 4. This indicates that MGRN 1‐dependent ubiquitination of an as‐yet unidentified target protein is required for agouti‐mediated melanocortin signaling.