Peptide splicing by the proteasome

The proteasome is the major protease responsible for the production of antigenic peptides recognized by CD8+ cytolytic T cells (CTL). These peptides, generally 8-to-10 amino acid-long, are presented at the cell surface by major histocompatibility complex (MHC) class I molecules. Although for years, these peptides were believed to solely derive from linear fragments of proteins, this concept was challenged several years ago by the isolation of anti-tumor CTL that recognized spliced peptides, i.e. peptides composed of fragments originally distant in the parental protein. The splicing process was shown to take place in the proteasome through a transpeptidation reaction involving an acyl-enzyme intermediate. Here, we review the different steps that led to the discovery of spliced peptides as well as the recent advances in the field, which uncover the unexpected importance of spliced peptides in the composition of the MHC class I repertoire.