INTERFERON-GAMMA INDUCES DIFFERENT SUBUNIT ORGANIZATIONS AND FUNCTIONAL DIVERSITY OF PROTEASOMES

To obtain information on the role of proteasomes in the immune system, we examined the effect of a major immunomodulatory cytokine, gamma in terferon (IFN-gamma), on the expressions, structures, and functions of proteasomes. IFN-gamma greatly increased the levels of the mRNAs enco ding LMP2 and LMP7, putative immuno-proteasome subunits encoded by gen es within the class II MHC region, and these two subunits synthesized were assembled completely into the proteasomal multi-subunit complex i n various types of human cells. The subunit organization of the protea some changed in response to IFN-gamma stimulation, due to assembly of newly synthesized subunits through up- and down-expressions of at leas t 6 proteasome genes including LMP2/LMP7 without change in the structu re of pre-existing proteasomes. Interestingly, IFN-gamma dramatically stimulated the trypsin-like and chymotrypsin-like activities of the mu ltifunctional proteasome and depressed the peptidylglutamyl-peptide-hy drolyzing activity, without affecting the activity for ATP-, ubiquitin dependent proteolysis. These results indicate that IFN-gamma modifies not only the structural organization of the proteasome, but also its f unctions. Based on these findings, we discuss the role in the antigen processing/presentation pathway of proteasomes with functional diversi ty acquired through alteration of their subunit assembly in response t o IFN-gamma stimulation.