title: MGRN1-dependent pigment-type switching requires its ubiquitination activity but not its interaction with TSG101 or NEDD4.
abstract: Mice lacking the E3 ubiquitin ligase mahogunin ring finger-1 (MGRN1) have a pleiotropic phenotype that includes spongiform neurodegeneration, embryonic patterning defects, and dark fur due to a defect in pigment-type switching. The only MGRN1 ubiquitination target identified to date is tumor susceptibility gene 101 (TSG101), a component of the endosomal trafficking machinery. Here, we show that MGRN1 also interacts with but does not ubiquitinate NEDD4, a HECT-domain ubiquitin ligase involved in endosomal trafficking. Using transgenesis in mice, we demonstrate that pigment-type switching likely requires MGRN1's ubiquitin ligase activity but not its ability to bind TSG101 or NEDD4. This indicates that MGRN1-dependent ubiquitination of an as-yet unidentified target protein is required for agouti-mediated melanocortin signaling.
authors.affiliation: McLaughlin Research Institute, Great Falls, MT, USA; Department of Biomedical Sciences, Cornell University, Ithaca, NY, USA. tmg@mri.montana.edu
authors.forename: Teresa M
authors.initials: TM
authors.lastname: Gunn
authors.forename: Derek
authors.initials: D
authors.lastname: Silvius
authors.forename: Pooneh
authors.initials: P
authors.lastname: Bagher
authors.forename: Kaihua
authors.initials: K
authors.lastname: Sun
authors.forename: Katherine K
authors.initials: KK
authors.lastname: Walker
mesh_terms: D000818:Animals; D004268:DNA-Binding Proteins / Q000378:metabolism*; D056827:Endosomal Sorting Complexes Required for Transport / Q000378:metabolism*; D057809:HEK293 Cells; D006801:Humans; D051379:Mice; D008822:Mice, Transgenic; D000075702:Nedd4 Ubiquitin Protein Ligases; D010858:Pigmentation; D011485:Protein Binding; D012880:Skin Pigmentation; D014157:Transcription Factors / Q000378:metabolism*; D019076:Transgenes / Q000235:genetics; D044767:Ubiquitin-Protein Ligases / Q000378:metabolism*; D054875:Ubiquitination; D000099177:Tsg101 Protein
chemical_list: D004268:DNA-Binding Proteins; D056827:Endosomal Sorting Complexes Required for Transport; D000075702:Nedd4 Ubiquitin Protein Ligases; D014157:Transcription Factors; D044767:Ubiquitin-Protein Ligases; D000099177:Tsg101 Protein; C000618483:Nedd4 protein, human; C000618461:Nedd4l protein, mouse; C470689:Mgrn1 protein, mouse