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J Immunol ; 191(8): 4020-8, 2013 Oct 15.
Article in English | MEDLINE | ID: mdl-24048903

ABSTRACT

The signal peptide peptidase (SPP) is an intramembrane cleaving aspartyl protease involved in release of leader peptide remnants from the endoplasmic reticulum membrane, hence its name. We now found a new activity of SPP that mediates liberation of C-terminal peptides. In our search for novel proteolytic enzymes involved in MHC class I (MHC-I) presentation, we found that SPP generates the C-terminal peptide-epitope of a ceramide synthase. The display of this immunogenic peptide-MHC-I complex at the cell surface was independent of conventional processing components like proteasome and peptide transporter TAP. Absence of TAP activity even increased the MHC-I presentation of this Ag. Mutagenesis studies revealed the crucial role of the C-terminal location of the epitope and "helix-breaking" residues in the transmembrane region just upstream of the peptide, indicating that SPP directly liberated the minimal 9-mer peptide. Moreover, silencing of SPP and its family member SPPL2a led to a general reduction of surface peptide-MHC-I complexes, underlining the involvement of these enzymes in Ag processing and presentation.


Subject(s)
Antigen Presentation , Aspartic Acid Endopeptidases/metabolism , Histocompatibility Antigens Class I/immunology , Membrane Proteins/metabolism , ATP-Binding Cassette Transporters/metabolism , Animals , Aspartic Acid Endopeptidases/genetics , Aspartic Acid Endopeptidases/immunology , Cell Line, Tumor , Endoplasmic Reticulum/metabolism , HEK293 Cells , HeLa Cells , Humans , Membrane Proteins/genetics , Membrane Proteins/immunology , Mice , Mutation , Oxidoreductases/metabolism , Peptides/immunology , RNA Interference , RNA, Small Interfering
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