Newly identified pair of proteasomal subunits regulated reciprocally by interferon gamma.

Abstract

SummaryInterferon (IFN) y induces replacements of the proteasomal subunits X and Y by LMP7 and LMP2, respectively, resulting in an alteration of the proteolytic specificity. We found a third pair ofproteasome subunits expressed reciprocally in response to IFN-y. Molecular cloning of a cDNA encoding one subunit designated as Z, downregulated by IFN-% showed that it is a novel proteasomal subunit with high homology to MECL1, which is markedly induced by IFN-% Thus, IFN-~/induces subunit replacements of not only X and Y by LMP7 and LMP2, respectively, but also of Z by MECL1, producing proteasomes responsible for immunological processing of endogenous antigens. When processed from their precursors, three pairs of the 10 homologous, but distinct, [3-type subunits of eukaryotic proteasomes, that is, X/LMP7, Y/LMP2, and Z/MECL1, have an NH2-terminal threonine residue, assumed to be part of a catalytic center. These findings suggest that the altered molecular organization of the proteasome induced by IFN-y may be responsible for acquisition of its functional change.

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“…48). Contrary to other strains (46,47), we found that expression of Psmb6 in the NOD M increases upon activation (Fig. 3), suggesting that exchange of Lmp-2 for Psmb6 in proteosomes may be strain dependent.…”

“…Upon IFN-␥ treatment, the Psmb6 subunit is replaced with its inducible partner, Lmp2, forming "immunoproteasomes" (46,47) that are believed to favor the generation of a "skewed" pool of peptides for MHC class I molecules, leading to an enhanced immune response against viral infections (reviewed in Ref. 48).…”

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“…The expression of these three unique subunits leads to the formation of a unique CP isoform in which the catalytic subunits β1, β2, and β5 are replaced with β1i, β2i, and β5i, respectively, as a result of the response to IFN-γ. In 1994, we proposed that the IFN-γ-inducible proteasome isotype should be called the "immunoproteasome" to emphasize its specialized roles as a dedicated antigen-processing enzyme in cell-mediated immunity 49,52,53 (Fig. 2, middle panel).…”