Casarosa P, Bakker R A, Verzijl D, Navis M, Timmerman H, Leurs R, Smit M J
Division of Medicinal Chemistry, Leiden/Amsterdam Center for Drug Research, Vrije Universiteit Amsterdam, 1081 HV Amsterdam, The Netherlands.
J Biol Chem. 2001 Jan 12;276(2):1133-7. doi: 10.1074/jbc.M008965200.
Previously it was shown that the HHV-8-encoded chemokine receptor ORF74 shows considerable agonist-independent, constitutive activity giving rise to oncogenic transformation (Arvanitakis, L., Geras-Raaka, E., Varma, A., Gershengorn, M. C., and Cesarman, E. (1997) Nature 385, 347-350). In this study we report that a second viral-encoded chemokine receptor, the human cytomegalovirus-encoded US28, also efficiently signals in an agonist-independent manner. Transient expression of US28 in COS-7 cells leads to the constitutive activation of phospholipase C and NF-kappaB signaling via G(q/11) protein-dependent pathways. Whereas phospholipase C activation is mediated via Galpha(q/11) subunits, the activation of NF-kappaB strongly depends on betagamma subunits with a preference for the beta(2)gamma(1) dimer. The CC chemokines RANTES (regulated on activation, normal T cell expressed and secreted) and MCP-1 (monocyte chemotactic protein-1) act as neutral antagonists at US28, whereas the CX(3)C chemokine fractalkine acts as a partial inverse agonist with IC(50) values of 1-5 nm. Our data suggest that a high level of constitutive activity might be a more general characteristic of viral G protein-coupled receptors and that human cytomegalovirus might exploit this G protein-coupled receptor property to modulate the homeostasis of infected cells via the early gene product US28.
先前的研究表明，人疱疹病毒8型（HHV-8）编码的趋化因子受体ORF74表现出相当程度的非激动剂依赖性组成性活性，可导致致癌转化（阿尔瓦尼塔基斯，L.，杰拉斯-拉阿卡，E.，瓦尔马，A.，格申戈尔恩，M.C.，和塞萨尔曼，E.（1997年）《自然》385卷，347 - 350页）。在本研究中，我们报告第二种病毒编码的趋化因子受体，即人巨细胞病毒编码的US28，也能以非激动剂依赖的方式有效发出信号。US28在COS - 7细胞中的瞬时表达通过G(q/11)蛋白依赖性途径导致磷脂酶C和NF-κB信号的组成性激活。虽然磷脂酶C的激活是通过Gα(q/11)亚基介导的，但NF-κB的激活强烈依赖于βγ亚基，尤其偏好β(2)γ(1)二聚体。CC趋化因子RANTES（活化调节正常T细胞表达和分泌）和MCP-1（单核细胞趋化蛋白-1）在US28上作为中性拮抗剂起作用，而CX(3)C趋化因子fractalkine作为部分反向激动剂，IC(50)值为1 - 5纳米。我们的数据表明，高水平的组成性活性可能是病毒G蛋白偶联受体更普遍的特征，并且人巨细胞病毒可能利用这种G蛋白偶联受体特性，通过早期基因产物US28来调节受感染细胞的内环境稳定。
