The MCMV immunoevasin gp40/m152 inhibits NKG2D receptor RAE-1γ by intracellular retention and cell surface masking

NKG2D is a crucial Natural Killer (NK) cell activating receptor, and the murine cytomegalovirus (MCMV) employs multiple immunoevasins in order to avoid NKG2D-mediated activation. One of the MCMV immunoevasins, gp40 (m152), downregulates the cell surface NKG2D ligand, RAE-1{gamma}, thus limiting NK cell activation. This study establishes the molecular mechanism by which gp40 retains RAE-1{gamma} in the secretory pathway. Using flow cytometry and pulse chase analysis, we demonstrate that gp40 retains RAE-1{gamma} in the early secretory pathway, and that this effect depends on the binding of gp40 to a host protein, TMED10, a member of the p24 protein family. We also show that the TMED10-based retention mechanism can be saturated, and that gp40 has a backup mechanism as it masks RAE-1{gamma} on the cell surface, blocking the interaction with the NKG2D receptor and thus NK cell activation. Summary statementMCMV immunoevasin gp40 inhibits the NKG2D-activating ligand RAE-1{gamma} by intracellular retention that depends on the p24 member TMED10, and additionally by masking it at the cell surface.