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Tight Linkage between Translation and MHC Class I Peptide Ligand Generation Implies Specialized Antigen Processing for Defective Ribosomal Products¹

Shu-Bing Qian^*, Eric Reits, Jacques Neefjes, Jeanne M. Deslich^*, Jack R. Bennink^* and Jonathan W. Yewdell^2,*

^* Laboratory of Viral Diseases, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD 20892; and Division of Tumor Biology, The Netherlands Cancer Institute, Amsterdam, The Netherlands

There is mounting evidence that MHC class I peptide ligands are predominantly generated from defective ribosomal products and other classes of polypeptides degraded rapidly (t_1/2 < 10 min) following their synthesis. The most direct evidence supporting this conclusion is the rapid inhibition of peptide ligand generation following cycloheximide-mediated inhibition of protein synthesis. In this study, we show that this linkage is due to depleting the pool of rapidly degraded proteins, and not to interference with other protein synthesis-dependent processes. Our findings indicate that in the model systems used in this study, MHC class I peptides are preferentially generated from rapidly degraded polypeptides relative to slowly degraded proteins. This conclusion is supported by the properties of peptide presentation from slowly degraded (t_1/2 = 4 h) defective ribosomal products generated artificially by incorporation of the amino acid analog canavanine into a model viral Ag. We propose that specialized machinery exists to link protein synthesis with class I peptide ligand generation to enable the rapid detection of viral gene expression.

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