Interferon-gamma inducible exchanges of 20S proteasome active site subunits: Why?

When cells are stimulated with the cytokines IFN-gamma or TNF-alpha, the sy nthesis of three proteasome subunits LMP2 (beta 1i), LMP7 (beta 5i), and ME CL-1 (beta 2i) is induced. These subunits replace the three subunits delta (beta1), MB1 (beta5), and Z (beta2), which bear the catalytically active si tes of the proteasome, during proteasome neosynthesis. The cytokine-induced exchanges of three active site subunits of a complex protease is unprecede nted in biology and one may expect a strong functional driving force for th is system to evolve. These cytokine-induced replacements of proteasome subu nits are believed to favour the production of peptide ligands of major hist ocompatibility complex (MHC) class I molecules for the stimulation of cytot oxic T cells. Although the peptide production by constitutive proteasomes i s able to maintain peptide-dependent MHC class I cell surface expression in the absence of LMP2 and LMP7, these subunits were recently shown to be piv otal for the generation or destruction of several unique epitopes. In this review we discuss the recent data on LMP2/LMP7/MECL-1-dependent epitope gen eration and the functions of each of these subunit exchanges. We propose th at these subunit exchanges have evolved not only to optimize class I peptid e loading but also to generate LMP2/LMP7/MECL-1-dependent epitopes in infla mmatory sites which are not proteolytically generated in uninflamed tissues . This difference in epitope generation may serve to better stimulate T cel ls in the sites of an ongoing immune response and to avoid autoimmunity in uninflamed tissues. (C) 2001 Societe francaise de biochimie et biologie mol eculaire / Editions scientifiques et medicales Elsevier SAS. All rights res erved.