The MHC class I ligand‐generating system: roles of immunoproteasomes and the interferon‐4gMY‐inducible proteasome activator PA28

Tanaka, Keiji; Kasahara, Masanori

doi:10.1111/j.1600-065x.1998.tb01195.x

Cited by 279 publications

(230 citation statements)

References 135 publications

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“…The majority of these peptides derive from the degradation of intracellular proteins by the proteasome [8]. In the presence of IFN-+ , the catalytic subunits g 1, g 2 and g 5 of the proteasome are replaced by their homologous subunits LMP2, MECL1 and LMP7 to form the so-called immunoproteasomes [9]. As a result, the spectrum of the produced antigenic peptides can vary.…”

Section: Introductionmentioning

confidence: 99%

The Toll‐like receptor ligand MALP‐2 stimulates dendritic cell maturation and modulates proteasome composition and activity

et al. 2004

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A 2-kDa synthetic derivative of the macrophage-activating lipopeptide (MALP-2) from Mycoplasma fermentans is a potent inducer of monocytes/macrophages and improves the immunogenicity of antigens co-administered by systemic and mucosal routes. Dendritic cells (DC) are the most potent antigen-presenting cells, which are able to prime naive T cells in vivo. To elucidate the underlying mechanisms of MALP-2 adjuvanticity, we analyzed its activity on bone marrow-derived murine DC. In vitro stimulation of immature murine DC with MALP-2 resulted in the induction of maturation with up-regulated expression of MHC class II, costimulatory (CD80, CD86) and adhesion (CD40, CD54) molecules. MALP-2 also enhances the secretion of cytokines (IL-1 § , IL-6 and IL-12), and increases DC stimulatory activity on naive and antigen-specific T cells. Further studies demonstrated that MALP-2 treatment of DC results in a dose-dependent shift from the protein pattern of proteasomes to immunoproteasomes (up-regulation of LMP2, LMP7 and MECL1), which correlates with an increased proteolytic activity. Thus, the adjuvanticity of MALP-2 can be mediated, at least in part, by the stimulation of DC maturation, which in turn leads to an improved antigen presentation. Therefore, MALP-2 is a promising molecule for the development of immune therapeutic or prophylactic interventions.

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Section: Introductionmentioning

confidence: 99%

The Toll‐like receptor ligand MALP‐2 stimulates dendritic cell maturation and modulates proteasome composition and activity

et al. 2004

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“…The 20S proteasome consists of 14 different protein subunits (Groll et al1997), of which only three have an active site (Groll et al 1997(Groll et al , 1999Heinemeyer et al 1997;Tanaka and Kasahara 1998) Tanaka and Kasahara 1998). Thus two forms of proteasome exist: the "immunoproteasome", which is expressed in cells stimulated by gamma interferon (IFN-g) or tumor necrosis factor alpha (TNF-a), and in primary and secondary lymphoid organs, and the "constitutive proteasome", which is expressed in healthy, normal tissues and in immune-privileged organs such as the brain (Dahlmann et al 2000;Noda et al 2000;Kuckelkorn et al 2002).…”

Section: Introductionmentioning

confidence: 99%

Bioinformatic analysis of functional differences between the immunoproteasome and the constitutive proteasome

et al. 2003

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Intracellular proteins are degraded largely by proteasomes. In cells stimulated with gamma interferon , the active proteasome subunits are replaced by "immuno" subunits that form immunoproteasomes. Phylogenetic analysis of the immunosubunits has revealed that they evolve faster than their constitutive counterparts. This suggests that the immunoproteasome has evolved a function that differs from that of the constitutive proteasome. Accumulating experimental degradation data demonstrate, indeed, that the specificity of the immunoproteasome and the constitutive proteasome differs. However, it has not yet been quantified how different the specificity of two forms of the proteasome are. The main question, which still lacks direct evidence, is whether the immunoproteasome generates more MHC ligands. Here we use bioinformatics tools to quantify these differences and show that the immunoproteasome is a more specific enzyme than the constitutive proteasome. Additionally, we predict the degradation of pathogen proteomes and find that the immunoproteasome generates peptides that are better ligands for MHC binding than peptides generated by the constitutive proteasome. Thus, our analysis provides evidence that the immunoproteasome has co-evolved with the major histocompatibility complex to optimize antigen presentation in vertebrate cells.

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“…A 19S regulatory complex binds as a "cap" to the top & bottom of the 20S core, to generate the mature 26S organelle. More than a decade ago, it was shown that the protein constitution of the proteasome underwent an IFNγ-induced alteration during viral infections, with the constitutive proteasomes being, largely, replaced by modified structures that were termed immunoproteasomes (reviewed, Tanaka and Kasahara, 1998;Niedermann, 2002). Structural comparison of the two proteasomal types revealed changes in three of the 14 proteins; the three catalytic components of the constitutive proteasome were replaced by new proteins named LMP2, LMP7 & LMP10 (MECL1), which also have catalytic activity.…”

Section: Introductionmentioning

confidence: 99%

Myelin oligodendrocyte glycoprotein peptide-induced experimental allergic encephalomyelitis and T cell responses are unaffected by immunoproteasome deficiency

Frausto

Crocker

Eam

et al. 2007

Journal of Neuroimmunology

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The inoculation of MOG peptides into C57BL/6 mice induces CD4 + and CD8 + T cells, and recent work has shown that adoptive transfer of the latter population, after extensive in vitro stimulation, can cause EAE in naïve recipient mice. Herein, we have evaluated the incidence and severity of EAE, and the induction of CD4 + and CD8 + T cells, following MOG peptide inoculation of wt mice and of LMP-2KO mice that lack an intact immunoproteasome, a cytoplasmic organelle that is induced by chronic inflammation and that may be important for the presentation of MHC class I epitopes to CD8 + T cells. We report that EAE, evaluated by both clinical and histological criteria, is similar in LMP-2KO mice and wildtype C57B/6 mice (wt) in response to immunization with MOG peptides MOG 35-55 and MOG [40][41][42][43][44][45][46][47][48][49][50][51][52][53][54] , suggesting that the immunoproteasome does not play a key role in the development of demyelinating disease. Furthermore, and consistent with previous reports, peptidespecific CD8 + T cells were barely detectable in the CNS of peptide-immunized mice, although peptide-specific CD4 + T cells were abundant. Therefore, we used a new technique to look for autoreactive CD8 + T cells in MOG peptide-immunized mice, and we report the identification of CD4 + and CD8 + T cells that, as late as 19 days after peptide injection, are actively producing IFNγ in vivo, in response to in vivo antigen contact.

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The MHC class I ligand‐generating system: roles of immunoproteasomes and the interferon‐4gMY‐inducible proteasome activator PA28

Cited by 279 publications

References 135 publications

The Toll‐like receptor ligand MALP‐2 stimulates dendritic cell maturation and modulates proteasome composition and activity

The Toll‐like receptor ligand MALP‐2 stimulates dendritic cell maturation and modulates proteasome composition and activity

Bioinformatic analysis of functional differences between the immunoproteasome and the constitutive proteasome

Myelin oligodendrocyte glycoprotein peptide-induced experimental allergic encephalomyelitis and T cell responses are unaffected by immunoproteasome deficiency

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