Intramembrane proteolysis of signal peptides: An essential step in the generation of HLA-E epitopes

Signal sequences of human MHC class I molecules are a unique source of epit opes for newly synthesized nonclassical HLA-E molecules. Binding of such co nserved peptides to HLA-E induces its cell surface expression and protects cells from NK cell attack. After cleavage from the pre-protein, we show tha t the liberated NMC class I signal peptide is further processed by signal p eptide peptidase in the hydrophobic, membrane-spanning region. This cut is essential for the release of the HLA-E epitope-containing fragment from the lipid bilayer and its subsequent transport into the lumen of the endoplasm ic reticulum. via the TAP.