The specificity of proteasomes: impact on MHC class I processing and presentation of antigens

Abstract

We have studied polypeptide processing by purified proteasomes, with regard to proteolytic specificity and cytotoxic T-lymphocyte (CTL) epitope generation. Owing to defined preferences with respect to cleavage sites and fragment length, proteasomes degrade polypeptide substrates into cohorts of overlapping oligopeptides. Many of the proteolytic fragments exhibit structural features in common with major histocompatibility complex (MHC) class I ligands including fragment size and frequencies of amino acids at fragment boundaries. Proteasomes frequently generate definitive MHC class I ligands and/or slightly longer peptides, while substantially larger peptides are rare. Individual CTL epitopes are produced in widely varying amounts, often consistent with immunohierarchies among CTL epitopes. We further found that polypeptide processing is remarkably conserved among proteasomes of eukaryotic origin and that invertebrate proteasomes can efficiently produce known high-copy MHC class I ligands, suggesting evolutionary adaptation of the transporter associated with antigen processing and MHC class I to ancient constraints imposed by proteasomal protein degradation.

Similar Intracellular Peptide Profile of TAP1/β2 Microglobulin Double-Knockout Mice and C57BL/6 Wild-Type Mice as Revealed by Peptidomic Analysis

“…In eukaryotic cells, most proteins destined for degradation are initially tagged with a polyubiquitin chain in an energy-dependent process and then digested into peptides containing two to 20 amino acids by the 26S proteasome, which is a large proteolytic complex involved in the regulation of cell division, gene expression, and other key processes (37,38). Thus, the concomitant action of proteasomes and other extra lysosomal proteolytic systems (3,39) at different intracellular locations means that there is continuous formation and release of free peptides within mammalian cells (5,6). Intriguingly, very little is known about the identity of the intracellular peptides formed during normal protein turnover, and these are thought to be rapidly destroyed by amino peptidases that release amino acids for de novo protein synthesis.…”

Simplified Synthetic TMC‐95A/B Analogues Retain the Potency of Proteasome Inhibitory Activity

“…[4,13] A small fraction of the peptides generated by the proteasome are presented by major histocompatibility complex class I molecules on the cell surface, and thus play a role in immune surveillance. [14][15][16][17] Therefore, inhibitors that selectively block proteolytic activities of the proteasome are of therapeutic potential for the treatment of cancer, inflammatory disorders, and immune diseases. [18][19][20] Many proteasome inhibitors have been developed, such as synthetic peptide aldehydes, [1] boronates, [21] or vinylsulfones, [22] as well as the natural products lactacystin [23] and epoxomicin.…”

Induction of G1 Arrest and Apoptosis in Human Jurkat T Cells by Pentagalloylglucose through Inhibiting Proteasome Activity and Elevating p27Kip1, p21Cip1/WAF1, and Bax Proteins

“…Its catalytic core, referred as the 20 S proteasome, is a threonine protease containing at least three distinct proteolytic activities: chymotrypsin-like, trypsin-like, and peptidylglutamyl peptide-hydrolyzing (PGPH) 1 activities (4,5). Proteasomal degradation of proteins is critical for the regulation of cellular function and homeostasis such as progression of the cell cycle (6), apoptosis (7,8), oncogenesis (9 -11), transcription (12), cell adhesion (13), migration (14), angiogenesis (15), antigen presentation (16), and selective elimination of abnormal proteins.…”