Human MC4R variants affect endocytosis, trafficking and dimerization revealing multiple cellular mechanisms involved in weight regulation.

• 发表时间: 03 2021 23
• 来源期刊: Cell Rep
• DOI: 10.1016/j.celrep.2021.108862
• PMID: 33761344
• 文章类型: Journal Article
• 作者列表: Brouwers B,de Oliveira EM,Marti-Solano M,Monteiro FBF,Laurin SA,Keogh JM,Henning E,Bounds R,Daly CA,Houston S,Ayinampudi V,Wasiluk N,Clarke D,Plouffe B,Bouvier M,Babu MM,Farooqi IS,Mokrosiński J

关键词: GPCRs; Gα(s); MC4R; MSH; melanocortin; obesity; therapy; weight loss; β-arrestin

Abstract

The Melanocortin-4 Receptor (MC4R) plays a pivotal role in energy homeostasis. We used human MC4R mutations associated with an increased or decreased risk of obesity to dissect mechanisms that regulate MC4R function. Most obesity-associated mutations impair trafficking to the plasma membrane (PM), whereas obesity-protecting mutations either accelerate recycling to the PM or decrease internalization, resulting in enhanced signaling. MC4R mutations that do not affect canonical Gαs protein-mediated signaling, previously considered to be non-pathogenic, nonetheless disrupt agonist-induced internalization, β-arrestin recruitment, and/or coupling to Gαs, establishing their causal role in severe obesity. Structural mapping reveals ligand-accessible sites by which MC4R couples to effectors and residues involved in the homodimerization of MC4R, which is disrupted by multiple obesity-associated mutations. Human genetic studies reveal that endocytosis, intracellular trafficking, and homodimerization regulate MC4R function to a level that is physiologically relevant, supporting the development of chaperones, agonists, and allosteric modulators of MC4R for weight loss therapy.