Abstract
Two members of the proteasome activator, PA28alpha and PA28beta, form a heteropolymer that binds to both ends of the 20S proteasome. Evidence in vitro indicates that this interferon-gamma (IFN-gamma)-inducible heteropolymer is involved in the processing of intracellular antigens, but its functions in vivo remain elusive. To investigate the role of PA28alpha/beta in vivo, we generated mice deficient in both PA28alpha and PA28beta genes. The ATP-dependent proteolytic activities were decreased in PA28alpha(-/-)/beta(-/-) cells, suggesting that 'hybrid proteasomes' are involved in protein degradation. Treatment of PA28alpha(-/-)/beta(-/-) cells with IFN-gamma resulted in sufficient induction of the 'immunoproteasome'. Moreover, splenocytes from PA28alpha(-/-)/beta(-/-) mice displayed no apparent defects in processing of ovalbumin. These results are in marked contrast to the previous finding that immunoproteasome assembly and immune responses were impaired in PA28beta(-/-) mice. PA28alpha(-/-)/beta(-/-) mice also showed apparently normal immune responses against infection with influenza A virus. However, they almost completely lost the ability to process a melanoma antigen TRP2-derived peptide. Hence, PA28alpha/beta is not a prerequisite for antigen presentation in general, but plays an essential role for the processing of certain antigens.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Adenosine Triphosphate / metabolism
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Animals
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Antigen Presentation / drug effects
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Antigen Presentation / physiology*
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Autoantigens
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Cysteine Endopeptidases / biosynthesis*
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Cysteine Endopeptidases / immunology*
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Egg Proteins / immunology
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Epitopes / immunology
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Immunodominant Epitopes / immunology
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Influenza A virus / immunology
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Intramolecular Oxidoreductases / genetics
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Intramolecular Oxidoreductases / immunology
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Mice
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Mice, Knockout
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Mice, Mutant Strains
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Multienzyme Complexes / biosynthesis*
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Multienzyme Complexes / immunology*
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Organ Specificity / drug effects
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Organ Specificity / physiology
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Ovalbumin / immunology
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Peptide Fragments
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Peptide Hydrolases
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Proteasome Endopeptidase Complex
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Proteins / genetics
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Proteins / metabolism
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RNA, Messenger / metabolism
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T-Lymphocytes / cytology
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T-Lymphocytes / immunology
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T-Lymphocytes / metabolism
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T-Lymphocytes, Cytotoxic / cytology
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T-Lymphocytes, Cytotoxic / immunology
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T-Lymphocytes, Cytotoxic / metabolism
Substances
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Autoantigens
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Egg Proteins
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Epitopes
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Immunodominant Epitopes
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Ki antigen
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Multienzyme Complexes
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OVA-8
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Peptide Fragments
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Proteins
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RNA, Messenger
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Adenosine Triphosphate
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Ovalbumin
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Peptide Hydrolases
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Cysteine Endopeptidases
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Proteasome Endopeptidase Complex
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Psme1 protein, mouse
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Psme2 protein, mouse
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Intramolecular Oxidoreductases
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dopachrome isomerase