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RNA polymerase II inhibitors dissociate antigenic peptide generation from normal viral protein synthesis: a role for nuclear translation in defective ribosomal product synthesis?
- Source :
-
Journal of immunology (Baltimore, Md. : 1950) [J Immunol] 2010 Dec 01; Vol. 185 (11), pp. 6728-33. Date of Electronic Publication: 2010 Nov 03. - Publication Year :
- 2010
-
Abstract
- Following viral infection, cells rapidly present peptides from newly synthesized viral proteins on MHC class I molecules, likely from rapidly degraded forms of nascent proteins. The nature of these defective ribosomal products (DRiPs) remains largely undefined. Using inhibitors of RNA polymerase II that block influenza A virus neuraminidase (NA) mRNA export from the nucleus and inhibit cytoplasmic NA translation, we demonstrate a surprising disconnect between levels of NA translation and generation of SIINFEKL peptide genetically inserted into the NA stalk. A 33-fold reduction in NA expression is accompanied by only a 5-fold reduction in K(b)-SIINFEKL complex cell-surface expression, resulting in a net 6-fold increase in the overall efficiency of Ag presentation. Although the proteasome inhibitor MG132 completely blocked K(b)-SIINFEKL complex generation, we were unable to biochemically detect a MG132-dependent cohort of NA DRiPs relevant for Ag processing, suggesting that a minute population of DRiPs is a highly efficient source of antigenic peptides. These data support the idea that Ag processing uses compartmentalized translation, perhaps even in the nucleus itself, to increase the efficiency of the generation of class I peptide ligands.
- Subjects :
- Active Transport, Cell Nucleus drug effects
Active Transport, Cell Nucleus genetics
Active Transport, Cell Nucleus immunology
Animals
Antigen Presentation genetics
Antigen Presentation immunology
Antigens, Viral genetics
Antigens, Viral metabolism
Cell Line
Dogs
HeLa Cells
Humans
Influenza A virus drug effects
Influenza A virus enzymology
Influenza A virus immunology
L Cells
Mice
Neuraminidase antagonists & inhibitors
Neuraminidase biosynthesis
Neuraminidase genetics
Ovalbumin biosynthesis
Peptide Biosynthesis genetics
Peptide Fragments biosynthesis
Protein Biosynthesis drug effects
RNA, Messenger antagonists & inhibitors
RNA, Messenger biosynthesis
RNA, Messenger metabolism
Ribosomal Proteins biosynthesis
Ribosomal Proteins genetics
Viral Proteins genetics
Viral Proteins metabolism
Antigens, Viral biosynthesis
DNA-Directed RNA Polymerases antagonists & inhibitors
Dichlororibofuranosylbenzimidazole pharmacology
Peptide Biosynthesis drug effects
Peptide Biosynthesis immunology
Protein Biosynthesis immunology
Ribosomal Proteins deficiency
Viral Proteins biosynthesis
Subjects
Details
- Language :
- English
- ISSN :
- 1550-6606
- Volume :
- 185
- Issue :
- 11
- Database :
- MEDLINE
- Journal :
- Journal of immunology (Baltimore, Md. : 1950)
- Publication Type :
- Academic Journal
- Accession number :
- 21048111
- Full Text :
- https://doi.org/10.4049/jimmunol.1002543