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
Division of Medicinal Chemistry, Amsterdam Institute for Molecular and Life Sciences, Vrije Universiteit Amsterdam, de Boelelaan 1108, 1081 HZ Amsterdam, the Netherlands.
Department Pathology, Cancer Center Amsterdam, VU University Medical Center, de Boelelaan 1118, Amsterdam 1081 HZ, the Netherlands.
iScience. 2023 Jul 18;26(8):107412. doi: 10.1016/j.isci.2023.107412. eCollection 2023 Aug 18.
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 CXCL1 and CCL5, and US28-containing exosomes inhibited the CXCL1-CXCR1 signaling axis. These findings suggest that exosomal release of US28 contributes to chemokine scavenging and immune evasion by HCMV.
人类巨细胞病毒（HCMV）编码的趋化因子受体US28在病毒生命周期的各个方面发挥作用，并通过从HCMV感染细胞的微环境中清除趋化因子来促进免疫逃逸。与大多数人类趋化因子受体定位于质膜不同，US28主要定位于细胞内。在本研究中，我们使用免疫荧光和电子显微镜来确定外源性表达时以及在HCMV感染细胞中US28的定位。我们观察到US28定位于称为多囊泡体（MVBs）的晚期内体区室，在那里它被分选到腔内小泡中。活细胞全内反射荧光（TIRF）显微镜显示，含有US28的MVBs可以与质膜融合，导致US28在外泌体上分泌。外泌体US28结合趋化因子CXCL1和CCL5，并且含有US28的外泌体抑制CXCL1-CXCR1信号轴。这些发现表明，US28的外泌体释放有助于HCMV清除趋化因子和免疫逃逸。
