Virion display reveals MD-1 as an endogenous agonist for the orphan receptor GPRC5B

One-third of all nonodorant G protein–coupled receptors (GPCRs) in humans are orphans with no known ligands. Deorphanization of these GPCRs is hampered by the difficulty of producing purified receptors in their native conformations and the lack of a proteome-wide, high-throughput screening approach. Here, we validated a generalizable strategy to deorphanize multipass membrane receptors in the human genome. We leveraged virion display technology to produce recombinant viruses that displayed the four orphan receptors in the GPRC5 family and used them as probes against a human proteome array to identify potential protein ligands. We focused on GPRC5B, a GPCR previously implicated in obesity and metabolic dysfunction. We found that the glycoprotein myeloid differentiation 1 (MD-1) was a ligand that selectively activated GPRC5B on adipocytes, leading to signaling mediated by Gα s . The binding of MD-1 to GPRC5B on differentiated 3T3-L1 adipocytes stimulated lipolysis, an effect that was maximally induced by cell-cell contact with MD-1–expressing RAW 264.7 macrophages. Macrophage infiltration into adipose tissue is a common hallmark of obesity and is associated with dysregulated adipose tissue function, and our findings define a signaling axis that regulates lipolysis in a manner dependent on adipocyte-macrophage interactions.