Natalia Lis

• 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. My study establishes the molecular mechanism by which gp40 retains RAE-1 gamma in the secretory pathway. Using flow cytometry and pulse chase analysis, I 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. I 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.