DRiPs solidify: progress in understanding endogenous MHC class I antigen processing

Abstract

Defective ribosomal products (DRiPs) are a subset of rapidly degraded polypeptides that provide peptide ligands for major histocompatibility complex (MHC) class I molecules. Here, recent progress in understanding DRiP biogenesis is reviewed. These findings place DRiPs at the center of the MHC class I antigen processing pathway, linking immunosurveillance of viruses and tumors to mechanisms of specialized translation and cellular compartmentalization. DRiPs enable the immune system to rapidly detect alterations in cellular gene expression with great sensitivity.

Figure 1. Idealized Kinetic Analysis of Antigen Presentation

Depicted are graphs of cells expressing a source antigen at a uniform rate starting at time zero. (a) presentation kinetics. If antigenic peptides derive exclusively from rapidly degraded DRiPs, the substrate pool will reach steady state rapidly and class I complexes will be generated at linear kinetics from near time zero, with a lag dependent on the time for degradation, loading, and transport from the site of loading in the secretory pathway. If peptides derive exclusively from retirees, there will be a much longer lag prior to detection on the cell surface, and the rate of complex delivery will accelerate over a much longer time, as the pool of substrate reaches its steady state level. (b) and (c) presentation shut off kinetics. From adding various inhibitors, half-lives can be calculated for antigen presentation. BFA provides a measure of the transit time from post-BFA sensitive compartments to the cell surface. Proteasome inhibitors provide a measure of the time for peptide loading and transport to the cell surface. Protein synthesis inhibitors provide a measure of the half-life of the relevant substrate pool. If peptides derive from DRiPs, blocking protein synthesis will rapidly shut off delivery of pMHC I complexes to the cell surface (b). If peptides derive from long lived retirees, blocking protein synthesis will have no effect on complex delivery to the plasma membrane, at least as long as cells maintain a sufficient supply of class I molecules in the ER, likely to be the limiting factor in continue antigen presentation.