Abstract
Human cytomegalovirus (HCMV) is a widespread pathogen that infects up to 80% of the human population and causes severe complications in immunocompromised patients. HCMV expresses four seven transmembrane (7TM) spanning/G protein-coupled receptors (GPCRs) - US28, US27, UL33 and UL78 - that show close homology to human chemokine receptors. While US28 was shown to bind several chemokines and to constitutively activate multiple signaling cascades, the function(s) of US27, UL33 and UL78 in the viral life cycle have not yet been identified. Here we investigated the possible interaction/heteromerization of US27, UL33 and UL78 with US28 and the functional consequences thereof. We provide evidence that these receptors not only co-localize, but also heteromerize with US28 in vitro. While the constitutive activation of the US28-mediated Gαq/phospholipase C pathway was not affected by receptor heteromerization, UL33 and UL78 were able to silence US28-mediated activation of the transcription factor NF-κB. Summarized, we provide evidence that these orphan viral receptors have an important regulatory capacity on the function of US28 and as a consequence, may ultimately impact on the viral life cycle of HCMV.