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Signal."],"published-print":{"date-parts":[[2026,6,16]]},"abstract":"<jats:p>\n                    One-third of all nonodorant G protein\u2013coupled 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 G\u03b1\n                    <jats:sub>s<\/jats:sub>\n                    . 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\u2013expressing 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.\n                  <\/jats:p>","DOI":"10.1126\/scisignal.adr8554","type":"journal-article","created":{"date-parts":[[2026,6,16]],"date-time":"2026-06-16T17:58:16Z","timestamp":1781632696000},"update-policy":"https:\/\/doi.org\/10.34133\/aaas_crossmark","source":"Crossref","is-referenced-by-count":0,"title":["Virion display reveals MD-1 as an endogenous agonist for the orphan receptor GPRC5B"],"prefix":"10.1126","volume":"19","author":[{"ORCID":"https:\/\/orcid.org\/0009-0008-9541-552X","authenticated-orcid":true,"given":"Eric","family":"Johansen","sequence":"first","affiliation":[{"name":"Department of Physiology, Pharmacology and Therapeutics, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4661-414X","authenticated-orcid":true,"given":"Guan-Da","family":"Syu","sequence":"additional","affiliation":[{"name":"Department of Physiology, Pharmacology and Therapeutics, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA."},{"name":"Department of Biotechnology and Bioindustry Sciences, National Cheng Kung University, Tainan, Taiwan."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7923-6451","authenticated-orcid":true,"given":"Zijian","family":"Wan","sequence":"additional","affiliation":[{"name":"Center for Bioelectronics and Biosensors, Biodesign Institute, Arizona State University, Tempe, AZ 85287, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Dylan C.","family":"Sarver","sequence":"additional","affiliation":[{"name":"Department of Physiology, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA."},{"name":"Center for Metabolism and Obesity Research, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0002-8408-5541","authenticated-orcid":true,"given":"Meng","family":"Ding","sequence":"additional","affiliation":[{"name":"Department of Physiology, Pharmacology and Therapeutics, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9750-7718","authenticated-orcid":true,"given":"Xinzhong","family":"Dong","sequence":"additional","affiliation":[{"name":"Solomon H. Snyder Department of Neuroscience, Department of Neurosurgery, Center for Sensory Biology, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA."},{"name":"Howard Hughes Medical Institute, Chevy Chase, MD 20815, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2680-0503","authenticated-orcid":true,"given":"Shaopeng","family":"Wang","sequence":"additional","affiliation":[{"name":"Center for Bioelectronics and Biosensors, Biodesign Institute, Arizona State University, Tempe, AZ 85287, USA."},{"name":"School of Biological and Health Systems Engineering, Arizona State University, Tempe, AZ 85287, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5286-6506","authenticated-orcid":true,"given":"G. William","family":"Wong","sequence":"additional","affiliation":[{"name":"Department of Physiology, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA."},{"name":"Center for Metabolism and Obesity Research, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8426-2889","authenticated-orcid":true,"given":"Heng","family":"Zhu","sequence":"additional","affiliation":[{"name":"Department of Physiology, Pharmacology and Therapeutics, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"221","reference":[{"key":"e_1_3_2_2_2","doi-asserted-by":"publisher","DOI":"10.1038\/nrd2518"},{"key":"e_1_3_2_3_2","doi-asserted-by":"publisher","DOI":"10.1124\/mol.117.111062"},{"key":"e_1_3_2_4_2","doi-asserted-by":"publisher","DOI":"10.1038\/nrd.2017.178"},{"key":"e_1_3_2_5_2","doi-asserted-by":"publisher","DOI":"10.1038\/sj.bjp.0707606"},{"key":"e_1_3_2_6_2","doi-asserted-by":"publisher","DOI":"10.1124\/molpharm.124.000900"},{"key":"e_1_3_2_7_2","doi-asserted-by":"publisher","DOI":"10.1021\/ac401795y"},{"key":"e_1_3_2_8_2","doi-asserted-by":"publisher","DOI":"10.1038\/s41467-019-09938-9"},{"key":"e_1_3_2_9_2","doi-asserted-by":"publisher","DOI":"10.1074\/mcp.O111.016253"},{"key":"e_1_3_2_10_2","doi-asserted-by":"publisher","DOI":"10.1006\/geno.2000.6226"},{"key":"e_1_3_2_11_2","doi-asserted-by":"publisher","DOI":"10.1126\/scisignal.2003149"},{"key":"e_1_3_2_12_2","doi-asserted-by":"publisher","DOI":"10.1038\/s41586-021-03819-2"},{"key":"e_1_3_2_13_2","doi-asserted-by":"publisher","DOI":"10.2337\/db11-1182"},{"key":"e_1_3_2_14_2","doi-asserted-by":"publisher","DOI":"10.4049\/jimmunol.161.3.1348"},{"key":"e_1_3_2_15_2","doi-asserted-by":"publisher","DOI":"10.1038\/nsmb.3014"},{"key":"e_1_3_2_16_2","doi-asserted-by":"publisher","DOI":"10.1038\/s41589-020-0535-8"},{"key":"e_1_3_2_17_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.ymeth.2021.10.009"},{"key":"e_1_3_2_18_2","doi-asserted-by":"publisher","DOI":"10.3389\/fnins.2022.891544"},{"key":"e_1_3_2_19_2","doi-asserted-by":"publisher","DOI":"10.1146\/annurev.nutr.27.061406.093734"},{"key":"e_1_3_2_20_2","doi-asserted-by":"publisher","DOI":"10.1124\/molpharm.120.000192"},{"key":"e_1_3_2_21_2","doi-asserted-by":"publisher","DOI":"10.1111\/tra.12119"},{"key":"e_1_3_2_22_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.jmb.2011.09.020"},{"key":"e_1_3_2_23_2","doi-asserted-by":"publisher","DOI":"10.1111\/imm.13002"},{"key":"e_1_3_2_24_2","doi-asserted-by":"publisher","DOI":"10.1172\/JCI200319246"},{"key":"e_1_3_2_25_2","doi-asserted-by":"publisher","DOI":"10.1128\/jvi.67.3.1357-1364.1993"},{"key":"e_1_3_2_26_2","doi-asserted-by":"publisher","DOI":"10.1126\/science.1062191"},{"key":"e_1_3_2_27_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.xpro.2022.101259"},{"key":"e_1_3_2_28_2","doi-asserted-by":"publisher","DOI":"10.1161\/01.ATV.0000183883.72263.13"},{"key":"e_1_3_2_29_2","doi-asserted-by":"publisher","DOI":"10.1161\/01.ATV.0000251608.09329.9a"}],"container-title":["Science Signaling"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.science.org\/doi\/pdf\/10.1126\/scisignal.adr8554","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,6,16]],"date-time":"2026-06-16T17:58:18Z","timestamp":1781632698000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.science.org\/doi\/10.1126\/scisignal.adr8554"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,6,16]]},"references-count":28,"journal-issue":{"issue":"942","published-print":{"date-parts":[[2026,6,16]]}},"alternative-id":["10.1126\/scisignal.adr8554"],"URL":"https:\/\/doi.org\/10.1126\/scisignal.adr8554","relation":{},"ISSN":["1945-0877","1937-9145"],"issn-type":[{"value":"1945-0877","type":"print"},{"value":"1937-9145","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,6,16]]},"assertion":[{"value":"2024-07-18","order":0,"name":"received","label":"Received","group":{"name":"publication_history","label":"Publication History"}},{"value":"2025-06-02","order":1,"name":"revised","label":"Revised","group":{"name":"publication_history","label":"Publication History"}},{"value":"2026-05-28","order":2,"name":"accepted","label":"Accepted","group":{"name":"publication_history","label":"Publication History"}},{"value":"2026-06-16","order":3,"name":"published","label":"Published","group":{"name":"publication_history","label":"Publication History"}}],"article-number":"eadr8554"}}