How antigenic peptides are made to fit their groove

Abstract

The immune system is able detect and eliminate virus-infected cells by recognition of viral-derived peptides that are displayed at the cell surface. The proteasome generates these peptides by degradation of viral proteins in the cytosol. The peptides are then transported into the lumen of the endoplasmic reticulum (ER), where they bind to the major histocompatibility (MHC) class I complex. Assembly with the appropriate peptide in the ER leads to transport of the loaded MHC class I complex to the cell surface.Antigenic peptides produced by proteasomal cleavage often have N-terminal extensions that need to be removed, by an as yet unidentified aminopeptidase, for efficient antigen presentation. An attractive hypothesis is that such peptides are trimmed to their optimal length when their C terminus is already bound to the MHC class I complex; thus, each peptide would be ‘custom-tailored’ for an optimal fit in the specific binding groove to which it is attached. Two recent papers provide data that support this custom-tailoring in situ.Komlosh and colleagues1xA role for a novel luminal endoplasmic reticulum aminopeptidase in final trimming of 26S proteasome-generated major histocompatibility complex class I antigenic peptides. Komlosh et al. J. Biol. Chem. 2001; 276: 30050–30056Crossref | PubMed | Scopus (31)See all References1 found that an N-terminally extended peptide generated by proteasomal cleavage in vitro is processed to its optimal length in the presence of ER-derived microsomes. Processing was dependent on the activity of the transporter for antigenic peptides in the ER membrane, and on the presence of an MHC class I complex that can bind this specific peptide. In addition, N-terminal peptide trimming was inhibited by the metallo-aminopeptidase inhibitor 1,10-phenanthroline. Brouwenstijn et al.2xMHC class I molecules can direct proteolytic cleavage of antigenic precursors in the endoplasmic reticulum. Brouwenstijn et al. Immunity. 2001; 15: 95–104Abstract | Full Text | Full Text PDF | PubMed | Scopus (50)See all References2 made similar observations, but also went one step further: they showed that the N-terminally extended peptides, as well as the trimmed peptides, are bound to the MHC class I complex. If trimming was inhibited chemically by the aminopeptidase inhibitor LMCK, or by depletion of ER lumenal contents, only extended peptides co-immunoprecipitated with the MHC class I complex.Taken together, these data suggest that a soluble aminopeptidase in the ER lumen is responsible for the trimming of MHC class I bound antigenic peptides. The ER lumen is the site of secretory protein biogenesis, and contains a high concentration of folding intermediates that are protease-sensitive. The activity of the trimming N-peptidase therefore must be strictly controlled to prevent it from chewing on proteins that are in the process of folding. This could be achieved by coupling the activity of the peptidase to its interaction with the loaded MHC class I complex or, perhaps, with tapasin – a specific chaperone involved in peptide loading. Purification and characterization of the trimming aminopeptidase will surely shed light on these questions.