Signal peptide cleavage of a type I membrane protein, HCMV US11, is dependent on its membrane anchor

The human cytomegalovirus (HCMV) US11 polypeptide is a type I membrane glycoprotein that targets major histocompatibility complex (MHC) class I molecules for destruction in a proteasome‐dependent manner. Although the US11 signal sequence appears to be a classical N‐terminal signal peptide in terms of its sequence and cleavage site, a fraction of newly synthesized US11 molecules retain the signal peptide after the N‐linked glycan has been attached and translation of the US11 polypeptide has been completed. Delayed cleavage of the US11 signal peptide is determined by the first four residues, the so‐called n‐region of the signal peptide. Its replacement with the four N‐terminal residues of the H‐2K b signal sequence eliminates delayed cleavage. Surprisingly, a second region that affects the rate and extent of signal peptide cleavage is the transmembrane region close to the C‐terminus of US11. Deletion of the transmembrane region of US11 (US11‐180) significantly delays processing, a delay overcome by replacement with the H‐2K b signal sequence. Thus, elements at a considerable distance from the signal sequence affect its cleavage.