Impaired Immunoproteasome Assembly and Immune Responses in
            <i>
              PA28
              <sup>−/−</sup>
            </i>
            Mice

Preckel, Tobias; Fung-Leung, Wai-Ping; Cai, Zeling; Vitiello, Antonella; Salter–Cid, Luisa; Winqvist, Ola; Wolfe, Tom; Herrath, Matthias von; Angulo, Ana; Ghazal, Peter; Lee, Jiing Dwan; Fourie, Anne M.; Wu, Ying; Pang, Jesse Chung Sean; Ngo, Karen; Peterson, Per A.; Früh, Klaus; Yang, Young Mok

doi:10.1126/science.286.5447.2162

Cited by 162 publications

(119 citation statements)

References 21 publications

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“…Alternatively, immunosubunit incorporation could influence the substrate accessibility via the regulatory particles PA700 or PA28ab. Indeed, mice lacking PA28b demonstrated impaired immunosubunit incorporation into 20S proteasomes (44), although these results could not be confirmed in mice lacking both PA28a and PA28b (24). Our results suggest a more simple explanation as to how the structural features of immunosubunits can influence CTL epitope generation.…”

Section: Discussionmentioning

confidence: 60%

Why the Structure but Not the Activity of the Immunoproteasome Subunit Low Molecular Mass Polypeptide 2 Rescues Antigen Presentation

Basler

Lauer

Moebius

et al. 2012

The Journal of Immunology

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The proteasome is responsible for the generation of most epitopes presented on MHC class I molecules. Treatment of cells with IFN-γ leads to the replacement of the constitutive catalytic subunits β1, β2, and β5 by the inducible subunits low molecular mass polypeptide (LMP) 2 (β1i), multicatalytic endopeptidase complex-like-1 (β2i), and LMP7 (β5i), respectively. The incorporation of these subunits is required for the production of numerous MHC class I-restricted T cell epitopes. The structural features rather than the proteolytic activity of an immunoproteasome subunit are needed for the generation of some epitopes, but the underlying mechanisms have remained elusive. Experiments with LMP2-deficient splenocytes revealed that the generation of the male HY-derived CTL-epitope UTY246–254 was dependent on LMP2. Treatment of male splenocytes with an LMP2-selective inhibitor did not reduce UTY246–254 presentation, whereas silencing of β1 activity increased presentation of UTY246–254. In vitro degradation experiments showed that the caspase-like activity of β1 was responsible for the destruction of this CTL epitope, whereas it was preserved when LMP2 replaced β1. Moreover, inhibition of the β5 subunit rescued the presentation of the influenza matrix 58–66 epitope, thus suggesting that a similar mechanism can apply to the exchange of β5 by LMP7. Taken together, our data provide a rationale why the structural property of an immunoproteasome subunit rather than its activity is required for the generation of a CTL epitope.

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Section: Discussionmentioning

confidence: 60%

Why the Structure but Not the Activity of the Immunoproteasome Subunit Low Molecular Mass Polypeptide 2 Rescues Antigen Presentation

Basler

Lauer

Moebius

et al. 2012

The Journal of Immunology

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“…Immunoproteasomes contain an IFN-g inducible regulatory unit called the proteasome activator PA28 (Rock and Goldberg 1999;Kloetzel 2001). PA28 on its own can influence antigen presentation drastically, mainly by changing the kinetics of the degradation process without altering the specificity (Preckel et al 1999;Stohwasser et al 2000;Van Hall et al 2000;Kloetzel 2001;Sijts et al 2002;Sun et al 2002). Moreover, the immunoproteasomes, unlike constitutive proteasomes, may co-localize with TAP and thus increase MHC class I antigen presentation (Brooks et al 2000).…”

Section: Discussionmentioning

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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“…Whether these differences are attributable to the absence of LMP7 alone, or are compounded by reduced LMP2 and MECL1 incorporation in LMP7 Ϫ/Ϫ mice (23), is not clear. However, PA28b Ϫ/Ϫ mice have normal class I expression despite a defect in immunoproteasome assembly (42). Interestingly, while LMP2 and MECL1 are not incorporated into proteasomes in these mice, LMP7 is incorporated, albeit at reduced levels.…”

Section: Figmentioning

confidence: 97%

“…A third possibility is that other accessory proteins are involved in immunoproteasome assembly. In this regard, it was recently shown that PA28a and PA28b associate with preimmunoproteasomes, and in the absence of PA28b (PA28b Ϫ/Ϫ mice) recovery of these complexes is reduced, as is the incorporation of immunoproteasome subunits (42). This raises the possibility that the role of PA28 in proteasome assembly may involve binding to the ␣-ring and inducing a conformational change that makes preproteasomes more receptive to LMP2 and/or MECL1.…”

Section: Figmentioning

confidence: 97%

Novel Propeptide Function in 20 S Proteasome Assembly Influences β Subunit Composition

Kingsbury

Griffin

Colbert

2000

Journal of Biological Chemistry

101

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The assembly of eukaryotic 20 S proteasomes involves the formation of half-proteasomes where precursor ␤-type subunits gather in position on an ␣-subunit ring, followed by the association of two half-proteasomes and ␤-subunit processing. In vertebrates three additional ␤-subunits (␤1i/LMP2, ␤2i/MECL1, and ␤5i/LMP7) can be synthesized and substituted for constitutive homologues (␤1/delta, ␤2/Z, and ␤5/X) to yield immunoproteasomes, which are important for generating certain antigenic peptides. We have shown previously that when all six ␤-subunits are present, cooperative assembly mechanisms limit the diversity of proteasome populations. Specifically, LMP7 is incorporated preferentially over X into preproteasomes containing LMP2 and MECL1. We show here that the LMP7 propeptide is responsible for this preferential incorporation, and it also enables LMP7 to incorporate into proteasomes containing delta and Z. In contrast, the X propeptide restricts incorporation to proteasomes with delta and Z. Furthermore, we demonstrate that the LMP7 propeptide can function in trans when expressed on LMP2, and that its NH 2 -terminal and mid-regions are particularly critical for function. In addition to identifying a novel propeptide function, our results raise the possibility that one consequence of LMP7 incorporation into both immunoproteasomes and delta/Z proteasomes may be to increase the diversity of antigenic peptides that can be generated.

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Impaired Immunoproteasome Assembly and Immune Responses in PA28 ^−/− Mice

Cited by 162 publications

References 21 publications

Why the Structure but Not the Activity of the Immunoproteasome Subunit Low Molecular Mass Polypeptide 2 Rescues Antigen Presentation

Why the Structure but Not the Activity of the Immunoproteasome Subunit Low Molecular Mass Polypeptide 2 Rescues Antigen Presentation

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

Novel Propeptide Function in 20 S Proteasome Assembly Influences β Subunit Composition

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Impaired Immunoproteasome Assembly and Immune Responses in PA28 −/− Mice

Cited by 162 publications

References 21 publications

Why the Structure but Not the Activity of the Immunoproteasome Subunit Low Molecular Mass Polypeptide 2 Rescues Antigen Presentation

Why the Structure but Not the Activity of the Immunoproteasome Subunit Low Molecular Mass Polypeptide 2 Rescues Antigen Presentation

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

Novel Propeptide Function in 20 S Proteasome Assembly Influences β Subunit Composition

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Product

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Impaired Immunoproteasome Assembly and Immune Responses in PA28 ^−/− Mice