Rapid degradation of a large fraction of newly synthesized proteins by proteasomes

MHC class I molecules function to present peptides eight to ten residues lo ng to the immune system. These peptides originate primarily from a cytosoli c pool of proteins through the actions of proteasomes(1), and are transport ed into the endoplasmic reticulum, where they assemble with nascent class I molecules(2). Most peptides are generated from proteins that are apparentl y metabolically stable. To explain this, we previously proposed that peptid es arise from proteasomal degradation of defective ribosomal products (DRiP s). DRiPs are polypeptides that never attain native structure owing to erro rs in translation or post-translational processes necessary for proper prot ein folding(3). Here we show, first, that DRiPs constitute upwards of 30% o f newly synthesized proteins as determined in a variety of cell types; seco nd, that at least some DRiPs represent ubiquitinated proteins; and last, th at ubiquitinated DRiPs are formed from human immunodeficiency virus Gag pol yprotein, a long-lived viral protein that serves as a source of antigenic p eptides.