The Journal of Immunology, 2008,
181,
3731
Copyright © 2008 by The American Association of Immunologists, Inc.
Comment on "Characterizing the N-Terminal Processing Motif of MHC Class I Ligands"
Camilo A. L. S. Colaco
ImmunoBiology Limited, Cambridge, United Kingdom
In a recent article, Schatz et al. (1) characterized the N-terminal processing motif of MHC class I ligands. They demonstrated that this motif comprised approximately seven residues that matched the known preferences of proteasome and TAP, consistent with the view that these peptide ligands are the product of an intracellular pathway comprising protein breakdown in the cytosol and transport into the endoplasmic reticulum (ER). Furthermore, they also found that this was not true for residues immediately preceding the N terminus of MHC class I ligands and suggested, based on experimentally determined aminopeptidase activities, that trimming next to the final N terminus takes place predominantly in the ER. This is consistent with the proposed role of the ER-resident aminopeptidase ERAAP in the trimming to the canonical nonamer ligand length and whose role in immunity has been clearly shown in the ERAAP knockout mouse model (2). While this presents an almost complete picture of MHC class I loading, there remain a couple of unanswered questions: 1) the paucity of signal/leader sequences among MHC class I ligands, even though these should be the predominant peptide species; and 2) the lack of ligands longer than nonamers in the mature MHC class I molecules in the ERAAP knockout mouse. An intriguing possibility that is consistent with the findings of the Schatz et al. article and would answer both of these questions is that the cellular function of ERAAP is actually the degradation of signal/leader peptides generated in the ER during the synthesis of secreted and membrane proteins. The immunological consequence of this cellular function of ERAAP would be the tipping of the balance of loaded peptides away from cellular proteins to peptides that are more likely to be derived from endogenously synthesized pathogen antigens, a balance that would be inverted in the ERAAP knockout mice. The proposed cellular role for ERAAP would explain the paucity of host protein signal sequences in the population of bound peptides isolated from mature MHC class I molecules and untrimmed peptides larger than nonamers bound to class I even in ERAAP knockout cells, as well as suggest a possible identity for some minor histocompatibility antigens.
References
- Schatz, M. M., B. Peters, N. Akkad, N. Ullrich, A. N. Martinez, O. Carroll, S. Bulik, H.-G. Rammensee, P. van Endert, H.-G. Holzhütter, et al 2008. Characterizing the N-terminal processing motif of MHC class I ligands. J. Immunol. 180: 3210-3217. [Abstract/Free Full Text]
- Blanchard, N., N. Shastri. 2008. Coping with the loss of perfection in the MHC class I peptide repertoire. Curr. Opin. Immunol. 20: 82-88. [Medline]
