Upon targeting and translocation, the gpUL40 precursor (pre-gpUL40) is cleaved by SPase. The liberated SP (SPUL40) remains anchored in the membrane. Proposed association of the hydrophobic N-terminal segment (yellow box labeled *) with the membrane, and subsequent flipping of the hydrophilic spacer (green) and the c-region (blue) are indicated. The canonical n- and h-region are indicted in yellow (h) and red (n), respectively. In semi-intact cells, SPUL40 is further processed by an SPP-type intramembrane protease. The consensus HLA-E-binding peptide is delivered to the ER in a TAP-independent manner, where it binds and stabilizes both endogenous HLA-E and the HCMV-encoded MHC-I homologue gpUL18.