The C-X-C motif chemokine receptor type 4 (CXCR4) and the atypical chemokine receptor 3 (ACKR3/CXCR7) are class A G protein-coupled receptors (GPCRs). Accumulating evidence indicates that GPCR subcellular localization, trafficking, transduction properties, and ultimately their pathophysiological functions are regulated by both interacting proteins and post-translational modifications. This has encouraged the development of novel techniques to characterize the GPCR interactome and to identify residues subjected to post-translational modifications, with a special focus on phosphorylation. This review first describes state-of-the-art methods for the identification of GPCR-interacting proteins and GPCR phosphorylated sites. In addition, we provide an overview of the current knowledge of CXCR4 and ACKR3 post-translational modifications and an exhaustive list of previously identified CXCR4- or ACKR3-interacting proteins. We then describe studies highlighting the importance of the reciprocal influence of CXCR4/ACKR3 interactomes and phosphorylation states. We also discuss their impact on the functional status of each receptor. These studies suggest that deeper knowledge of the CXCR4/ACKR3 interactomes along with their phosphorylation and ubiquitination status would shed new light on their regulation and pathophysiological functions.
European Union’s Horizon2020 MSCA European Union’s Horizon2020 MSCA Program [Grant agreement 641833 (ONCORNET)]; A.F. and P.M. are also supported by CNRS, INSERM, Université de Montpellier and Fondation pour la Recherche Médicale (FRM); F.M. laboratory is also supported by grants from Ministerio de Economía; Industria y Competitividad (MINECO) of Spain [Grant SAF2017-84125-R]; CIBERCV-Instituto de Salud Carlos III, Spain [Grant CB16/11/00278] to F.M., cofunded with European FEDER contribution); Comunidad de Madrid-B2017/BMD-3671-INFLAMUNE; and Fundación Ramón Areces. Program [Grant agreement 641833 (ONCORNET)]; A.F. and P.M. are also supported by CNRS, INSERM, Université de Montpellier and Fondation pour la Recherche Médicale (FRM); F.M. laboratory is also supported by grants from Ministerio de Economía; Industria y Competitividad (MINECO) of Spain [Grant SAF2017-84125-R]; CIBERCV-Instituto de Salud Carlos III, Spain [Grant CB16/11/00278] to F.M., cofunded with European FEDER contribution); Comunidad de Madrid-B2017/BMD-3671-INFLAMUNE; and Fundación Ramón Areces.