Leucine Aminopeptidase Is Not Essential for Trimming Peptides in the Cytosol or Generating Epitopes for MHC Class I Antigen Presentation

Netherlands Cancer Institute, Amsterdamo, North Holland, Netherlands
The Journal of Immunology (Impact Factor: 4.92). 12/2005; 175(10):6605-14. DOI: 10.4049/jimmunol.175.10.6605
Source: PubMed


To detect viral infections and tumors, CD8+ T lymphocytes monitor cells for the presence of antigenic peptides bound to MHC class I molecules. The majority of MHC class I-presented peptides are generated from the cleavage of cellular and viral proteins by the ubiquitin-proteasome pathway. Many of the oligopeptides produced by this process are too long to stably bind to MHC class I molecules and require further trimming for presentation. Leucine aminopeptidase (LAP) is an IFN-inducible cytosolic aminopeptidase that can trim precursor peptides to mature epitopes and has been thought to play an important role in Ag presentation. To examine the role of LAP in generating MHC class I peptides in vivo, we generated LAP-deficient mice and LAP-deficient cell lines. These mutant mice and cells are viable and grow normally. The trimming of peptides in LAP-deficient cells is not reduced under basal conditions or after stimulation with IFN. Similarly, there is no reduction in presentation of peptides from precursor or full-length Ag constructs or in the overall supply of peptides from cellular proteins to MHC class I molecules even after stimulation with IFN. After viral infection, LAP-deficient mice generate normal CTL responses to seven epitopes from three different viruses. These data demonstrate that LAP is not an essential enzyme for generating most MHC class I-presented peptides and reveal redundancy in the function of cellular aminopeptidases.

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Available from: Margaret Karow, Jul 10, 2014
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    • "Moreover, MHC class I levels at the cellmembrane were reduced after overexpression of TOP, there is more than just recycling beyond the proteasome and was increased upon inhibition of TOP with siRNA [51]. LAP is involved in N-terminal trimming of antigenic peptides [52] as it removes single amino acids from the N-terminus of larger peptides and can generate the model epitope SIINFEKL [52]. Although LAP can generate specific epitopes, LAP-deficient mice showed no differences in MHC class I levels when compared to wild-type mice [53], suggesting that LAP activity is not essential for antigen processing. "
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    • "The peptides are then delivered to MHC I for antigen presentation to cytotoxic T-cells. While LAP clearly processes antigenic peptides in vitro (Beninga et al., 1998), analysis of LAP-knockout mice indicates that LAP activity is not essential for antigen presentation in vivo, suggesting that other aminopeptidases must be functionally redundant with LAPs (Towne et al., 2005). "
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