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

Area of Science:

• Immunology
• Molecular Biology
• Cellular Biology

Background:

• Qa-1b and HLA-E present leader peptides from other class I molecules.
• This presentation is dependent on the transporter associated with antigen processing (TAP) but independent of the proteasome.

Purpose of the Study:

• To elucidate the mechanism of Qa-1b and HLA-E mediated antigen presentation of leader peptides.
• To investigate the role of the transporter associated with antigen processing (TAP) in this pathway.

Main Methods:

• Utilized herpes simplex virus ICP-47 to block TAP-dependent peptide transport.
• Investigated peptide epitope generation in the cytosol and endoplasmic reticulum (ER).

Main Results:

• Dd targeted to the cytosol, even with proteasome inhibition (lactacystin), did not generate the Qa-1b epitope.
• ICP-47 expression blocked epitope generation, confirming TAP's role in transporting peptides from the cytosol to the ER.
• Demonstrated a novel pathway involving protein translocation to the ER, leader cleavage, cytosolic release, and TAP-mediated retro-transport into the ER.

Conclusions:

• A new pathway for antigen presentation of leader peptides is described, involving ER translocation, cleavage, and TAP-mediated retro-transport.
• This pathway ensures that Qa-1b expression accurately reflects the normal expression of class Ia molecules.