Quantifying the Contribution of Defective Ribosomal Products to Antigen Production: A Model-Based Computational Analysis

Abstract

Antigenic peptides (epitopes) presented on the cell surface by MHC class I molecules derive from proteolytic degradation of endogenous proteins. Some recent studies have proposed that the majority of epitopes stem from so-called defective ribosomal products (DRiPs), i.e., freshly synthesized proteins that are unable to adopt the native conformation and thus undergo immediate degradation. However, a reliable computational analysis of the data underlying this hypothesis was lacking so far. Therefore, we have applied kinetic modeling to derive from existing kinetic data (Princiotta et al. 2003, Immunity 18, 343–354) the rates of the major processes involved in the cellular protein turnover and MHC class I-mediated Ag presentation. From our modeling approach, we conclude that in these experiments 1) the relative share of DRiPs in the total protein synthesis amounted to ∼10% thus being much lower than reported so far, 2) DRiPs may become the decisive source of epitopes within an early phase after onset of the synthesis of a long-lived (e.g., virus derived) protein, and 3) inhibition of protein synthesis by the translation inhibitor cycloheximide appears to be paralleled with an instantaneous decrease of protein degradation down to ∼1/3 of the normal value.

Targeting HIV-1 Gag into the Defective Ribosomal Product Pathway Enhances MHC Class I Antigen Presentation and CD8+ T Cell Activation

“…Thus, an enhanced DRiP rate should result in an increased generation and steady-state level of antigenic peptides. DRiPs as a source for antigenic peptides may become especially crucial for efficient MHC-I Ag presentation in early stages of viral infection during the onset of synthesis of viral proteins, especially of stable, structural proteins like the retroviral Gag polyproteins (65,66).…”

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

“…Indeed, this assumption was built into recent mathematical modeling (15) of the effect of CHX on generation of K b -SIINFEKL from NP-SIINFEKL-GFP constructs (6). We examined this possibility by pulse radiolabeling L-K b cells (L929 cells transfected with a cDNA encoding H-2K b ) for 5 min with […”

The DRiP hypothesis decennial: support, controversy, refinement and extension

“…Recently, Bulik et al [29] employed mathematical modeling to calculate the relative contribution of DRiPs versus SDPs to antigen processing using the data generated by Princiotta et al [15]. This is a welcome development, because modeling based on careful quantitation of antigen presentation is crucial for verifying qualitative conclusions regarding the underlying mechanisms.…”