New role of signal peptide peptidase to liberate C-terminal peptides for MHC class I presentation

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 proteo...

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Bibliographic Details
Published in:The Journal of immunology (1950) 2013-10, Vol.191 (8), p.4020-4028
Main Authors: Oliveira, Cláudia C, Querido, Bianca, Sluijter, Marjolein, de Groot, Anne F, van der Zee, Reno, Rabelink, Martijn J W E, Hoeben, Rob C, Ossendorp, Ferry, van der Burg, Sjoerd H, van Hall, Thorbald
Format: Article
Language:English
Subjects:
Animals
Antigen Presentation
Aspartic Acid Endopeptidases - genetics
Aspartic Acid Endopeptidases - immunology
Aspartic Acid Endopeptidases - metabolism
ATP-Binding Cassette Transporters - metabolism
Cell Line, Tumor
Endoplasmic Reticulum - metabolism
HEK293 Cells
HeLa Cells
Histocompatibility Antigens Class I - immunology
Humans
Membrane Proteins - genetics
Membrane Proteins - immunology
Membrane Proteins - metabolism
Mice
Mutation
Oxidoreductases - metabolism
Peptides - immunology
RNA Interference
RNA, Small Interfering
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Summary: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.
ISSN:0022-1767
1550-6606
DOI:10.4049/jimmunol.1301496