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Antigen Presentation Damage Limitation: New Role for Immunoproteasomes

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Antigen Presentation Damage Limitation: New Role for Immunoproteasomes RESEARCH HIGHLIGHTS ANTIGEN PRESENTATION Damage limitation: new role for immunoproteasomes New research published in Cell indi­ This study showed that IFN to involve the production of reactive cates that, in addition to promoting an stimulation induces the transient oxygen species during inflammation adaptive immune response through accumulation of polyubiquitylated that cause oxidant damage to nascent increased antigen presentation, proteins, levels of which peaked cellular proteins. The level of oxidized the main function of the immuno­ 4–12 hours after IFN stimulation proteins correlated with the level proteasome might be to protect cells and declined 24–48 hours after of polyubiquitylated proteins, and from the damaging side effects of an stimulation, concomitant with both were higher in cells that lacked innate inflammatory response. immunoproteasome induction. immunoproteasomes. Furthermore, Cellular protein homeostasis is IFNγ preferentially stimulated the the addition to IFN­stimulated cells maintained in eukaryotic cells by the synthesis of polyubiquitin chains that of an antioxidant, which prevents degradation of short­lived or defective were linked through lysine residue 48 protein oxidation, decreased the proteins that are targeted to the 26S (K48), and this depended on the accumulation of polyubiquitylated proteasome by polyubiquitylation. specific induction of the ubiquitin­ proteins. Immunoproteasome­ During an inflammatory response, conjugating enzyme UBE2L6. The deficient cells had greater accumula­ type I or type II interferon (IFN) transient increase in cellular levels tion of oxidized proteins after IFNγ stimulation alters the subunit compo­ of polyubiquitylated proteins was stimulation than wild­type cells. So, sition of the 26S proteasome to form also explained by the IFN­induced inflammation­induced oxidative the immunoproteasome, which is transient dissociation of the 26S stress triggers polyubiquitylation of thought to more efficiently generate proteasome and therefore decreased damaged proteins (aided by IFN­ MHC class I epitopes for presentation cellular proteasome activity until mediated upregulation of K48­linked to CD8+ T cells and the initiation of an the immunoproteasome was formed ubiquitylation activity) that leads to adaptive immune response. However, after 24 hours. their accelerated degradation by IFN­ various data indicate that the immuno­ In addition, the immunoprotea­ induced immunoproteasomes. So, proteasome might have a function some was shown to be more efficient by maintaining protein homeostasis, other than antigen processing; for at degrading polyubiquitylated immunoproteasomes also increase example, the absence of immuno­ substrates than the standard 26S pro­ the peptide supply for MHC class I proteasomes does not affect T cell teasome. Immunoproteasomes had antigen presentation. priming in some models. twofold higher substrate turnover The accumulation of oxidized than standard proteasomes in in vitro proteins after IFNγ treatment in cells degradation assays. Both in vitro and that lack the immunoproteasome in vivo, cells that were deficient for resulted in increased caspase activity immunoproteasome subunits were and increased susceptibility to an unable to efficiently clear the poly­ apoptosis inducer. The increase ubiquitylated proteins that in apoptosis as a result of immuno­ accumulated in response to proteasome deficiency was evident IFN, and this resulted in from the increased clinical score and the accumulation of protein earlier onset of symptoms (indicative aggregates after IFNγ of increased neuronal death) in mice stimulation that failed to be with experimental autoimmune cleared as in wild­type cells. encephalomyelitis, thus indicating the These results show that importance of immunoproteasomes the immunoproteasome for preserving cell viability during functions to clear the cell of inflammation. polyubiquitylated proteins Kirsty Minton that form during inflammatory conditions and thereby to prevent ORIGINAL RESEARCH PAPER Seifert, U. et al. the formation of disruptive Immunoproteasomes preserve protein homeostasis upon interferon-induced oxidative protein aggregates. IFN­induced stress. Cell 142, 613–624 (2010) polyubiquitylation was shown NATURE REVIEWS | IMMUNOLOGY VOLUME 10 | OCTOBER 2010 © 2010 Macmillan Publishers Limited. All rights reserved.
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