The proteasome activator 11 S REG (PA28) and Class I antigen presentation

There are two immune responses in vertebrates: humoral immunity is mediated by circulating antibodies, whereas cytotoxic T lymphocytes (CTL) confer ce llular immunity. CTL lyse infected cells upon recognition of cell-surface M HC Class I molecules complexed with foreign peptides. The displayed peptide s are produced in the cytosol by degradation of host proteins or proteins f rom intracellular pathogens that might be present. Proteasomes are cylindri cal multisubunit proteases that generate many of the peptides eventually tr ansferred to the cell surface for immune surveillance. In mammalian proteas omes, six active sites face a central chamber. As this chamber is sealed of f from the enzyme's surface, there must be mechanisms to promote entry of s ubstrates. Two protein complexes have been found to bind the ends of the pr oteasome and activate it. One of the activators is the 19 S regulatory comp lex of the 26 S proteasome; the other activator is '11 S REG' [Dubiel, Prat t, Ferrell and Rechsteiner (1992) J. Biol. Chem. 267, 22369-22377] or 'PA28 ' [Ma, Slaughter and DeMartino (1992) J. Biol. Chem. 267, 10515-10523]. Dur ing the past 7 years, our understanding of the structure of REG molecules h as increased significantly, but much less is known about their biological f unctions. There are three REG subunits, namely alpha, beta and gamma, Recom binant REG alpha forms a ring-shaped heptamer of known crystal structure. 1 1S REG is a heteroheptamer of alpha and beta subunits. REG gamma is also pr esumably a heptameric ring, and it is found in the nuclei of the nematode w ork Caenorhabditis elegans and higher organisms, where it may couple protea somes to other nuclear components. REGa and REG beta, which are abundant in vertebrate immune tissues, are located mostly in the cytoplasm. Synthesis of REG alpha and beta subunits is induced by interferon-gamma, and this has led to the prevalent hypothesis that REG alpha/beta hetero-oligomers play an important role in Class I antigen presentation. In the present review we focus on the structural properties of REG molecules and on the evidence th at REG alpha/beta functions in the Class I immune response.