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Institut für Immunologie, Johannes-Gutenberg-Universität Mainz, Mainz, Germany
The possibility that ERAAP plays a role in limiting the presentation of peptides derived from signal peptides may be tempting from an immunologist’s view. In eukaryotic cells, signal peptides have a mean length of 22 amino acids and are removed by signal peptide peptidases from the N terminus of their source proteins. As most membrane and secreted proteins harbor signal peptides, the removed signal peptides could theoretically compete with peptides processed by the classical MHC class I pathway and transported by TAP into the ER. Ribosomes synthesize 
66,666 proteins s–1 per cell (1); if 15–60% are cotranslationally translocated into the ER, this leads to the generation of 10,000–40,000 signal peptides per second. This is comparable to the number of TAP-transported peptides (in a normal cell, there are 10,000 TAP1/2 complexes that transport a total of 20,000–50,000 peptides per second (2)). However, TAP is part of the peptide loading complex, which facilitates direct loading of the transported peptides onto newly synthesized MHC class I molecules, while signal peptides are attacked by ER-resident peptidases. Additionally, especially in the mouse system, presentation of signal peptides should be extremely limited due to a simple mismatch of the specificities of signal peptidases, which cleave preferentially after the amino acids Ala, Gly, Ser, Cys, Thr, and Pro (as derived from the SignalP 3.0 Server and the training sets used for SignalP 2.0) (3), and MHC class I molecules, which preferentially bind peptides with hydrophobic or basic residues at the C terminus (4). An exception may be the human HLA-A*02 molecule, which can bind peptides with an alanine at the C terminus, and, indeed, we have recently contributed to the description of signal sequence-derived peptides on MHC class I ligands in TAP-deficient cells (5). Most of these ligands contain an alanine at their C terminus, and the major part of them is preferentially presented on the cell surface in the absence of TAP. Theoretically, signal peptides could also be cleaved by endopeptidases or carboxypeptidases in the ER that would generate peptides with different C termini; however, no such activity has yet been described.
Concerning the "lack of ligands longer than nonamers in the mature MHC class I molecules in the ERAAP knockout mouse" mentioned by Dr. Colaco, we prefer the interpretation of the data (6) by Blanchard and Shastri (7), who propose that many of the unstable and structurally unique peptide-MHC complexes presented by ERAAP-deficient cells are most likely N-terminally extended peptides (7).
References
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