Immunological Functions of the Proteasome

Abstract

The adaptive immune system has evolved in higher vertebrates to defend them efficiently against infections and perhaps also against cancer. Cytotoxic T lymphocytes (CTLs) represent one major type of antigen-specific immunocyte. CTL recognize peptides from infectious agents and tumor antigens bound to major histocompatibility complex (MHC) class I molecules, and lyse cells that display such MHC class I/peptide complexes at the cell surface. MHC class I-binding peptides are derived through the continuous proteolysis of polypeptides that are synthesized in the cytosol or reach the cytosol in other ways. Suitable peptides bind to the transporter associated with antigen processing (TAP) for translocation into the endoplasmic reticulum (ER), and peptides with an appropriate motif bind to newly synthesized MHC class I molecules. The newly formed MHC class I—peptide complexes then travel to the cell surface for recognition by CTLs (Fig. 1). Because the peptides preferred by TAP are the same size as those presented by the MHC class I molecules or are somewhat longer, the major steps in MHC class I antigen processing can be expected to occur in the cytosol. Proteasomes are highly abundant cytosolic and nuclear protease complexes that degrade most intracellular proteins in higher eukaryotes and appear to play the major role in the cytosolic steps of MHC class I antigen processing. This review summarizes the present knowledge of the role of proteasomes in antigen processing and the impact of proteasomal proteolysis on T cell-mediated immunity.