Human and viral chemokines differentially modulate G protein signaling, β-arrestin recruitment and chemotaxis mediated by the viral G protein-coupled receptor ORF74

Our comprehensive profiling of ORF74 chemokine ligands reveals ligand-dependent activation of canonical signaling pathways, including calcium mobilization, β-arrestin recruitment and chemotaxis. We confirm that ORF74 exhibits constitutive β-arrestin recruitment and, upon co-expression with CXCR4, is able to modulate CXCL12-CXCR4-mediated cell migration. These data highlight the complex chemokine-ORF74 interplay and will contribute to a better understanding of KSHV infection and pathology through multiple ORF74-dependent mechanisms.