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Abstract
The genesis of gene families by the capture of host genes and their subsequent duplication is a crucial process in the evolution of large DNA viruses. CD48 is a cell surface molecule that interacts via its N-terminal immunoglobulin (Ig) domain with the cell surface receptor 2B4 (CD244), regulating leukocyte cytotoxicity. We previously reported the presence of five CD48 homologs (vCD48s) in two related cytomegaloviruses, and demonstrated that one of them, A43, binds 2B4 and acts as a soluble CD48 decoy receptor impairing NK cell function. Here, we have characterized the rest of these vCD48s. We show that they are highly glycosylated proteins that display remarkably distinct features: divergent biochemical properties, cellular locations, and temporal expression kinetics. In contrast to A43, none of them interacts with 2B4. Consistent with this, molecular modeling of the N-terminal Ig domains of these vCD48s evidences notable changes as compared to CD48, suggesting that they interact with alternative targets. Accordingly, we demonstrate that one of them, S30, tightly binds CD2, a crucial T- and NK-cell adhesion and costimulatory molecule. Thus, our findings show how a key host immune receptor gene captured by a virus can be subsequently remodeled to evolve new immunoevasins with altered binding properties.
Highlights
Viral infections elicit a strong and broad reaction based on the coordinated action between the innate and adaptive immunity
It interacts with its natural ligand CD48, another signaling lymphocyte activation molecule (SLAM) family member and a glycosylphosphatidylinositol (GPI) anchored molecule, which is expressed on most hematopoietic cells
Our previous phylogenetic analysis indicated that the origin of these vCD48 genes was a unique event of gene capture from the genome of a New World (NW) monkey ancestor of
Summary
Viral infections elicit a strong and broad reaction based on the coordinated action between the innate and adaptive immunity In these responses, NK cells and T lymphocytes play a critical role in the successful recognition and elimination of virally infected cells [1,2,3]. 2B4 (CD244), a transmembrane protein belonging to the signaling lymphocyte activation molecule (SLAM) family, is crucially implicated in the regulation of leukocyte cytotoxicity and cytokine production [8,9]. It interacts with its natural ligand CD48, another SLAM family member and a glycosylphosphatidylinositol (GPI) anchored molecule, which is expressed on most hematopoietic cells. The binding of CD48 to 2B4 induces the phosphorylation of the cytoplasmic immunoreceptor tyrosine switch motifs (ITSMs) and the subsequent interaction of the SLAM-associated protein (SAP)
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