Peptide Diffusion, Protection, and Degradation in Nuclear and Cytoplasmic Compartments Before Antigen Presentation by MHC Class I

Antigenic peptides generated by the proteasome have to survive a peptidase-containing environment for presentation by MHC class I molecules. We have visualized the fate and dynamics of intracellular peptides in living cells. We show that peptides are distributed over two different but interconnected compartments, the cytoplasm and the nucleus, and diffuse rapidly through and between these compartments. Since TAP is excluded from the nuclear face of the nuclear envelope, nuclear peptides have to leave the nucleus to contact TAP. Thereby, these peptides encounter cytosolic peptidases that degrade peptides within seconds unless bound to chromatin. Since peptide degradation is far more efficient than translocation, many peptides will be lost for antigen presentation by MHC class I molecules.