Interferon-γ Induces Different Subunit Organizations and Functional Diversity of Proteasomes1

Abstract

To obtain information on the role of proteasomes in the immune system, we examined the effect of a major immunomodulatory cytokine, gamma interferon (IFN-gamma), on the expressions, structures, and functions of proteasomes. IFN-gamma greatly increased the levels of the mRNAs encoding LMP2 and LMP7, putative immuno-proteasome subunits encoded by genes within the class II MHC region, and these two subunits synthesized were assembled completely into the proteasomal multi-subunit complex in various types of human cells. The subunit organization of proteasome changed in response to IFN-gamma stimulation, due to assembly of newly synthesized subunits through up- and down-expressions of at least 6 proteasome genes including LMP2/LMP7 without change in the structure of pre-existing proteasomes. Interestingly, IFN-gamma dramatically stimulated the trypsin-like and chymotrypsin-like activities of the multifunctional proteasome and depressed the peptidylglutamyl-peptide-hydrolyzing 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 functions. Based on these findings, we discuss the role in the antigen processing/presentation pathway of proteasomes with functional diversity acquired through alteration of their subunit assembly in response to IFN-gamma stimulation.

Peptidase activities of proteasomes are differentially regulated by the major histocompatibility complex-encoded genes for LMP2 and LMP7.

“…Since the activity of the total proteasome population changed after incorporation of only small amounts of LMP2 or -7, these subunits must cause major alterations in peptidase activity. Thus, their expression can account for the changes in proteasome activity induced by interferon 7, and these findings lend further support to the proposed roles of LMPs in altering the nature of the peptides generated for antigen presentation.…”

“…These peptideprotein complexes are then transported to the cell surface for presentation to cytotoxic T cells (1,3). Recently, strong evidence has been obtained implicating the proteasome (multicatalytic proteinase complex) and the ATP-ubiquitindependent pathway (4) in the process of the generation of antigenic fragments (5)(6)(7)(8)(9)(10).…”

Keratinocyte differentiation induced by calcium, phorbol ester or interferon-γ elicits distinct changes in the retinoid signalling pathways

“…Although the reduction of mRNA precedes the loss of RARγ and RXRα protein, increased protein degradation appears to be involved since a proteasome inhibitor could potently restore the receptor proteins levels. Previous studies have reported that IFNγ increases proteasomal activity [46] but IFNγ also induced a differentiation process resembling an apoptotic pathway [47], which might result in the general loss of proteins. As with PMA, RARα was much less affected than RARγ/RXRα which incriminates proteasomal degradation of the heterodimer due to RA-induced activation [43].…”

Heat Shock Up-Regulates lmp2 and lmp7 and Enhances Presentation of Immunoproteasome-Dependent Epitopes

“…Only three of the ␤ subunits (two copies of each) are proteolytically active: ␦ (␤1), X (␤5), and Z (␤5). In cells stimulated by the proinflammatory cytokine IFN-␥, the composition of the proteasome is altered such that the three active ␤ subunits are replaced by inducible subunits: lmp2 (␤1i), lmp7 (␤5i), and mecl1 (␤2i) (12)(13)(14)(15)(16)(17). This modified proteasome is the immunoproteasome (18).…”