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 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.
Department of Clinical Oncology, Leiden University Medical Center, 2333 ZA Leiden, The Netherlands;
Cláudia C
CC
Oliveira
Bianca
B
Querido
Marjolein
M
Sluijter
Anne F
AF
de Groot
Reno
R
van der Zee
Martijn J W E
MJ
Rabelink
Rob C
RC
Hoeben
Ferry
F
Ossendorp
Sjoerd H
SH
van der Burg
Thorbald
T
van Hall
D018528:ATP-Binding Cassette Transporters / Q000378:metabolism; D000818:Animals; D017951:Antigen Presentation; D016282:Aspartic Acid Endopeptidases / Q000235:genetics / Q000276:immunology / Q000378:metabolism*; D045744:Cell Line, Tumor; D004721:Endoplasmic Reticulum / Q000378:metabolism; D057809:HEK293 Cells; D006367:HeLa Cells; D015395:Histocompatibility Antigens Class I / Q000276:immunology*; D006801:Humans; D008565:Membrane Proteins / Q000235:genetics / Q000276:immunology / Q000378:metabolism*; D051379:Mice; D009154:Mutation; D010088:Oxidoreductases / Q000378:metabolism; D010455:Peptides / Q000276:immunology; D034622:RNA Interference; D034741:RNA, Small Interfering
D018528:ATP-Binding Cassette Transporters; D015395:Histocompatibility Antigens Class I; D008565:Membrane Proteins; D010455:Peptides; D034741:RNA, Small Interfering; C479747:Trh4 protein, mouse; C477327:transporter associated with antigen processing (TAP); D010088:Oxidoreductases; C108138:dihydroceramide desaturase; D016282:Aspartic Acid Endopeptidases; C568855:SPPL2a protein, mouse; C460085:signal peptide peptidase