Exosomal release of the virus-encoded chemokine receptor US28 contributes to chemokine scavenging

• Published in: iScience 2023-08, Vol.26 (8), p.107412-107412, Article 107412
• Main Authors: Bebelman, Maarten P., Setiawan, Irfan M., Bergkamp, Nick D., van Senten, Jeffrey R., Crudden, Caitrin, Bebelman, Jan Paul M., Verweij, Frederik J., van Niel, Guillaume, Siderius, Marco, Pegtel, D. Michiel, Smit, Martine J.
• Format: Article
• Language: English
• Subjects: Cell biology; Cellular Biology; Immunology; Life Sciences
• ISSN: 2589-0042; 2589-0042
• DOI: 10.1016/j.isci.2023.107412

The human cytomegalovirus (HCMV)-encoded chemokine receptor US28 contributes to various aspects of the viral life cycle and promotes immune evasion by scavenging chemokines from the microenvironment of HCMV-infected cells. In contrast to the plasma membrane localization of most human chemokine receptors, US28 has a predominant intracellular localization. In this study, we used immunofluorescence and electron microscopy to determine the localization of US28 upon exogenous expression, as well as in HCMV-infected cells. We observed that US28 localizes to late endosomal compartments called multivesicular bodies (MVBs), where it is sorted in intraluminal vesicles. Live-cell total internal reflection fluorescence (TIRF) microscopy revealed that US28-containing MVBs can fuse with the plasma membrane, resulting in the secretion of US28 on exosomes. Exosomal US28 binds the chemokines CX3CL1 and CCL5, and US28-containing exosomes inhibited the CX3CL1-CX3CR1 signaling axis. These findings suggest that exosomal release of US28 contributes to chemokine scavenging and immune evasion by HCMV. [Display omitted] •US28 is sorted into the MVBs of human cytomegalovirus-infected cells•Exocytosis of US28-containing MVBs results in the secretion of US28 on exosomes•Exosomal US28 scavenges chemokines and inhibits human chemokine receptor activation Immunology; Cell biology.