A novel cytosolic class I antigen-processing pathway for endoplasmic-reticulum-targeted proteins.
Proteins bearing an endoplasmic reticulum (ER) leader are inserted into the ER followed by cleavage of the signal peptide. Major histocompatibility complex class I-restricted T-cell epitopes can be generated from these proteins by the proteasome after retrotranslocation into the cytosol. Here, we show that an HLA-A(*)0201-restricted epitope from prostate stem cell antigen contains the cleavage site of the ER signal peptidase. The resulting cleavage products fail to bind to HLA-A(*)0201 and are not recognized by T lymphocytes. As processing of prostate stem cell antigen by signal peptidase occurs immediately after co-translational insertion, the epitope must be processed from polypeptides that have never reached the ER. The processing of this epitope depends on the proteasome and the transporter associated with antigen processing and shows a novel pathway of class I processing that relies on the failure of ER-targeted proteins to reach their target compartment.
Schlosser
Eva
E
Division of Immunology, Department of Biology, Postbox M661, Universitatstrasse 10, University of Constance, Konstanz D-78457, Germany.
Otero
Carolina
C
Wuensch
Christine
C
Kessler
Benedikt
B
Edelmann
Mariola
M
Brunisholz
René
R
Drexler
Ingo
I
Legler
Daniel F
DF
Groettrup
Marcus
M
D017951:Antigen Presentation / Q000276:immunology* / Q000502:physiology; D000951:Antigens, Neoplasm; D002460:Cell Line; D004721:Endoplasmic Reticulum / Q000378:metabolism*; D058851:GPI-Linked Proteins; D015395:Histocompatibility Antigens Class I / Q000378:metabolism*; D006801:Humans; D008285:Major Histocompatibility Complex / Q000276:immunology / Q000502:physiology; D008562:Membrane Glycoproteins / Q000235:genetics / Q000378:metabolism; D008565:Membrane Proteins / Q000378:metabolism; D009363:Neoplasm Proteins / Q000235:genetics / Q000378:metabolism; D046988:Proteasome Endopeptidase Complex / Q000378:metabolism; D011993:Recombinant Fusion Proteins / Q000235:genetics / Q000378:metabolism; D012697:Serine Endopeptidases / Q000378:metabolism; D015398:Signal Transduction / Q000502:physiology*; D013602:T-Lymphocytes, Cytotoxic / Q000276:immunology / Q000378:metabolism; D014162:Transfection
D000951:Antigens, Neoplasm; D058851:GPI-Linked Proteins; D015395:Histocompatibility Antigens Class I; D008562:Membrane Glycoproteins; D008565:Membrane Proteins; D009363:Neoplasm Proteins; C110843:PSCA protein, human; D011993:Recombinant Fusion Proteins; D012697:Serine Endopeptidases; C026515:type I signal peptidase; D046988:Proteasome Endopeptidase Complex