The pathway for processing leader-derived peptides that regulate the maturation and expression of Qa-1b

Qa-1(b) and its human homolog, HLA-E, predominantly bind leader peptides derived from other class I molecules. Their presentation is TAP-dependent and proteasome-independent. We demonstrate that D-d targeted to the cytosol does not generate the Qa-1(b) peptide epitope even in the presence of lactacystin. Cells expressing herpes virus ICP-47 block the generation of this epitope, demonstrating that TAP functions in the transport of the peptide from cytosol to ER. This reveals a pathway for antigen presentation of leader peptides that involves translocation of a protein to the ER where its leader is cleaved followed by its release into the cytosol and transport back into the ER. Further, it ensures that Qa-1(b) expression mirrors the normal expression of class Ia molecules.