The divergent evolution of cytomegalovirus-encoded CD48 homologs contributes to the expansion of the immunevasin repertoire

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Abstract The genesis of gene families by capture of host genes and their subsequent duplication is a crucial process in the evolution of large DNA viruses. CD48 is a GPI-linked cell surface protein containing two extracellular immunoglobulin (Ig) domains. Via its N-terminal Ig domain, CD48 interacts with the cell surface receptor 2B4, modulating leukocyte cytotoxicity. We previously reported the presence of five CD48 homologs (vCD48s) in two related cytomegaloviruses, derived from a common host CD48 ancestor gene acquired by retrotranscription. Recently, we examined one member of this family, A43, showing that it acts as a functional viral decoy receptor, impairing 2B4-mediated NK cell cytotoxicity. Here, we have characterized the rest of the vCD48s. We show that they are highly glycosylated type I transmembrane proteins which display remarkably distinct structures, biochemical properties, locations, and temporal kinetic classes. Molecular modeling of the N-terminal Ig domains of these vCD48s evidence significant changes in the number and length of their β-strands and inter-sheet loops that participate in the interaction of CD48 with 2B4, and accordingly we found that none of these molecules binds to 2B4. Interestingly, we determined that two of them, S30 and S31, have new targets in T or B lymphocytes. In particular, S30 tightly interacts with CD2, a T- and NK-cell adhesion and costimulatory molecule whose primary ligand is CD58. Thus, altogether our results show how a key host immune receptor captured by a virus can be subsequently remodeled during viral evolution to yield new molecules with shifted binding specificities to additional immune targets, expanding the repertoire of viral immunevasins.