{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,25]],"date-time":"2026-09-25T05:00:03Z","timestamp":1790312403777,"version":"4.1.0"},"reference-count":37,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2026,9,25]],"date-time":"2026-09-25T00:00:00Z","timestamp":1790294400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Pharmacol."],"abstract":"<jats:p>\n                    Open reading frame 74 (ORF74) is the single G protein-coupled receptor (GPCR) encoded in the genome of Kaposi\u2019s sarcoma-associated herpesvirus (KSHV). Due to its high constitutive activity and broad chemokine binding profile, ORF74 contributes to KSHV-associated diseases through autocrine and paracrine mechanisms that promote cell proliferation, inflammation and angiogenesis. Previous studies showed that ELR+ CXC chemokines (i.e., CXCL1\u20133 and CXCL5\u20138), which contain a conserved Glu-Leu-Arg motif, bind ORF74 with high affinity. Among these chemokines, CXCL1\u20133 and CXCL6\u20138 act as full or partial agonists in ORF74-mediated G protein signaling and \u03b2-arrestin recruitment, whereas CXCL5 behaves as a neutral ligand. However, whether these chemokines preferentially engage specific intracellular transducers remains unclear. We therefore applied a unified NanoLuc Binary Technology (NanoBiT) platform in HEK293A\u00a0cells to systematically compare how ELR+ CXC chemokines modulate ORF74\u2013transducer proximity across the G protein\u2013GRK\u2013\u03b2-arrestin axis. CXCL1\u20133 and CXCL6\u20138, but not CXCL5, induced concentration-dependent ORF74-specific responses involving miniG\n                    <jats:sub>i<\/jats:sub>\n                    recruitment, G\u03b21 proximity, GRK2\/3\/5\/6 proximity and \u03b2-arrestin1\/2 recruitment. Using CXCL1 as the reference ligand, bias analysis showed that the active ELR+ CXC chemokines engage ORF74 in a largely balanced manner across these proximal transducer readouts.\n                  <\/jats:p>","DOI":"10.3389\/fphar.2026.1953308","type":"journal-article","created":{"date-parts":[[2026,9,25]],"date-time":"2026-09-25T04:27:31Z","timestamp":1790310451000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":0,"title":["High-affinity ELR+ CXC chemokines display balanced G protein-, GRK- and \u03b2-arrestin-associated transducer engagement at the viral G protein-coupled receptor ORF74"],"prefix":"10.3389","volume":"17","author":[{"given":"Qianqian","family":"Kong","sequence":"first","affiliation":[{"name":"Department of Microbiology, Immunology and Transplantation, Rega Institute for Medical Research, Molecular, Structural and Translational Virology Research Group, KU Leuven","place":["Leuven, Belgium"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Brent","family":"Van Bosstraeten","sequence":"additional","affiliation":[{"name":"Department of Microbiology, Immunology and Transplantation, Rega Institute for Medical Research, Molecular, Structural and Translational Virology Research Group, KU Leuven","place":["Leuven, Belgium"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Steven","family":"De Jonghe","sequence":"additional","affiliation":[{"name":"Department of Microbiology, Immunology and Transplantation, Rega Institute for Medical Research, Molecular, Structural and Translational Virology Research Group, KU Leuven","place":["Leuven, Belgium"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Dominique","family":"Schols","sequence":"additional","affiliation":[{"name":"Department of Microbiology, Immunology and Transplantation, Rega Institute for Medical Research, Molecular, Structural and Translational Virology Research Group, KU Leuven","place":["Leuven, Belgium"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tom","family":"Van Loy","sequence":"additional","affiliation":[{"name":"Department of Microbiology, Immunology and Transplantation, Rega Institute for Medical Research, Molecular, Structural and Translational Virology Research Group, KU Leuven","place":["Leuven, Belgium"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2026,9,25]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","first-page":"14","DOI":"10.1186\/1471-2164-12-14","article-title":"Expression of G protein-coupled receptors and related proteins in HEK293, AtT20, BV2, and N18 cell lines as revealed by microarray analysis","volume":"12","author":"Atwood","year":"2011","journal-title":"BMC Genom"},{"key":"B2","doi-asserted-by":"publisher","first-page":"287","DOI":"10.1038\/s42003-026-09568-0","article-title":"Cell-based and isoform-selective G protein-coupled receptor kinase assays for comprehensive inhibitor evaluation","volume":"9","author":"Blum","year":"2026","journal-title":"Commun. 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