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NIH grant 1R01DK144613-01A1: Regulation of ciliary trafficking of the Melanocortin 4 receptor by ubiquitination
Institute: {'code': 'DK', 'abbreviation': 'NIDDK', 'name': 'National Institute of Diabetes and Digestive and Kidney Diseases', 'admin_org_id': '12500020', 'admin_funding_url': ''}. PI: Maxence V Nachury. Award: $819556.
Start: 2026-08-27T00:00:00.
Project Summary/Abstract
We investigate the molecular and cellular mechanism underlying Melanocortin-4 Receptor (MC4R) activity-
dependent trafficking. MC4R is a G-protein coupled polypeptide receptor that is essential for body weight
regulation as demonstrated in particular by genetic studies in mice and humans. This receptor is also a target
for the pharmacological treatment of obesity.
We have found that this receptor localizes and functions at the primary cilia in vivo. Primary cilia are cell
surface projections that receive and transduce select intercellular signals. We have also demonstrated that
MC4R localization and function are dependent on the MC4R-associated protein MRAP2 and that upon
activation MC4R and MRAP2 exit cilia.
In order to study more precisely the mechanism by which active MC4R exits cilia we have established a
cellular model and have found that in this system, MC4R exit from the primary cilia requires β-arrestin and
ubiquitination.
Here we will combine studies in this cellular model as well as studies in vivo in mice to dissect the role of
MC4R and MRAP2 ubiquitination for ciliary exit, characterize the roles of β-arrestin and MC4R phosphorylation
in regulated exit of MC4R form cilia and determine the nature of the ubiquitin ligase complex that regulate
MC4R exit from cilia.document fetched 2026-09-06 02:47