title: Mahoganoid and mahogany mutations rectify the obesity of the yellow mouse by effects on endosomal traffic of MC4R protein.
abstract: The ubiquitous overexpression of agouti-signaling protein (ASP), a paracrine-signaling molecule that regulates pigment-type switching in the hair follicle of the mouse, is responsible for the obesity and yellow pelage of the Yellow mouse (A(y)). Mahogany (Attractin, Atrn/mg) and mahoganoid (Mahogunin Ring Finger-1, Mgrn1/md) are mutations epistatic to A(y). These mutations have been described as suppressors of ASP action, blocking its antagonizing effects on the melanocortin 1 and 4 receptors (MC1R and MC4R) in the skin and the brain, respectively, via unknown mechanisms. Here, we describe the molecular bases for the md- and mg-dependent rescue of the A(y) phenotype at the MC4R. We show that overexpression of ASP inhibits the rise in cAMP levels in response to α-melanocyte-stimulating hormone, an MC4R agonist, by blocking ligand binding and by directing MC4R trafficking to the lysosome. Loss-of-function of either attractin or MGRN1 blocks ASP-dependent MC4R degradation and promotes increased trafficking of internalized MC4R to the cell surface, but it does not restore α-melanocyte-stimulating hormone-dependent cAMP signaling. We propose that MGRN1 and attractin are components of an evolutionarily conserved receptor trafficking pathway and that the md and mg mutations rescue the A(y) phenotypes by a primarily cAMP-independent mechanism promoting trafficking of MC4R and likely MC1R away from the lysosome toward the cell surface.
authors: Division of Molecular Genetics, Department of Pediatrics, Naomi Berrie Diabetes Center and the Institute of Human Nutrition, Columbia University, New York, New York 10032, USA. john.overton@yale.edu
authors: John D
authors: JD
authors: Overton
authors: Rudolph L
authors: RL
authors: Leibel
mesh_terms: D054366:Agouti Signaling Protein / Q000235:genetics / Q000378:metabolism; D000818:Animals; D000242:Cyclic AMP / Q000235:genetics / Q000378:metabolism; D011992:Endosomes / Q000235:genetics / Q000378:metabolism*; D015870:Gene Expression / Q000235:genetics; D008565:Membrane Proteins / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D008817:Mice, Mutant Strains; D009154:Mutation; D009765:Obesity / Q000235:genetics / Q000378:metabolism*; D021381:Protein Transport / Q000235:genetics; D044102:Receptor, Melanocortin, Type 1 / Q000235:genetics / Q000378:metabolism; D044105:Receptor, Melanocortin, Type 4 / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction / Q000235:genetics; D044767:Ubiquitin-Protein Ligases / Q000235:genetics / Q000378:metabolism*; D000521:alpha-MSH / Q000235:genetics / Q000378:metabolism
chemical_list: D054366:Agouti Signaling Protein; C117928:Atrn protein, mouse; D008565:Membrane Proteins; D044102:Receptor, Melanocortin, Type 1; D044105:Receptor, Melanocortin, Type 4; C515183:a protein, mouse; D000521:alpha-MSH; D000242:Cyclic AMP; C470689:Mgrn1 protein, mouse; D044767:Ubiquitin-Protein Ligases