Surrogate antigen processing mediated by TAP-dependent antigenic peptide secretion.
MHC class I proteins assemble with peptides in the ER. The peptides are predominantly generated from cytoplasmic proteins, probably by the action of the proteasome, a multicatalytic proteinase complex. Peptides are translocated into the ER by the transporters associated with antigen processing (TAP), and bind to the MHC class I molecules before transport to the cell surface. Here, we use a new functional assay to demonstrate that peptides derived from vesicular stomatitis virus nucleoprotein (VSV-N) antigen are actively secreted from cells. This secretion pathway is dependent on the expression of TAP transporters, but is independent of the MHC genotype of the donor cells. Furthermore, the expression and transport of MHC class I molecules is not required. This novel pathway is sensitive to the protein secretion inhibitors brefeldin A (BFA) and a temperature block at 21 degrees C, and is also inhibited by the metabolic poison, azide, and the protein synthesis inhibitor, emetine. These data support the existence of a novel form of peptide secretion that uses the TAP transporters, as opposed to the ER translocon, to gain access to the secretion pathway. Finally, we suggest that this release of peptides in the vicinity of uninfected cells, which we term surrogate antigen processing, could contribute to various immune and secretory phenomena.
Gabathuler
R
R
Biotechnology Laboratory, University of British Columbia, Vancouver, British Columbia, Canada V6T1Z3.
Alimonti
J
J
Zhang
Q J
QJ
Kolaitis
G
G
Reid
G
G
Jefferies
W A
WA
D018528:ATP-Binding Cassette Transporters / Q000096:biosynthesis; D000818:Animals; D001386:Azides / Q000494:pharmacology; D020126:Brefeldin A; D002478:Cells, Cultured; D002522:Chlorocebus aethiops; D003517:Cyclopentanes / Q000494:pharmacology; D004640:Emetine / Q000494:pharmacology; D004721:Endoplasmic Reticulum / Q000187:drug effects / Q000378:metabolism; D005822:Genetic Vectors; D015395:Histocompatibility Antigens Class I / Q000096:biosynthesis*; D006801:Humans; D007739:L Cells; D051379:Mice; D008810:Mice, Inbred C57BL; D019251:Nucleocapsid / Q000096:biosynthesis / Q000276:immunology; D019590:Nucleocapsid Proteins; D011993:Recombinant Fusion Proteins / Q000096:biosynthesis; D018353:Rhabdoviridae Infections / Q000276:immunology; D013602:T-Lymphocytes, Cytotoxic / Q000187:drug effects / Q000276:immunology*; D014162:Transfection; D014407:Tumor Cells, Cultured; D014616:Vaccinia virus / Q000235:genetics; D014709:Vero Cells; D014721:Vesicular stomatitis Indiana virus / Q000235:genetics / Q000276:immunology
D018528:ATP-Binding Cassette Transporters; D001386:Azides; D003517:Cyclopentanes; D015395:Histocompatibility Antigens Class I; D019590:Nucleocapsid Proteins; D011993:Recombinant Fusion Proteins; D020126:Brefeldin A; D004640:Emetine