Immunoproteasome assembly and antigen presentation in mice lacking both PA28alpha and PA28beta.
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.
Murata
S
S
Department of Molecular Oncology, Tokyo Metropolitan Institute of Medical Science, and CREST, Japan Science and Technology Corporation, Tokyo 113-8613, Japan.
Udono
H
H
Tanahashi
N
N
Hamada
N
N
Watanabe
K
K
Adachi
K
K
Yamano
T
T
Yui
K
K
Kobayashi
N
N
Kasahara
M
M
Tanaka
K
K
Chiba
T
T
D000255:Adenosine Triphosphate / Q000378:metabolism; D000818:Animals; D017951:Antigen Presentation / Q000187:drug effects / Q000502:physiology*; D001324:Autoantigens; D003546:Cysteine Endopeptidases / Q000096:biosynthesis* / Q000276:immunology*; D004527:Egg Proteins / Q000276:immunology; D000939:Epitopes / Q000276:immunology; D016056:Immunodominant Epitopes / Q000276:immunology; D009980:Influenza A virus / Q000276:immunology; D019746:Intramolecular Oxidoreductases / Q000235:genetics / Q000276:immunology; D051379:Mice; D018345:Mice, Knockout; D008817:Mice, Mutant Strains; D009097:Multienzyme Complexes / Q000096:biosynthesis* / Q000276:immunology*; D009928:Organ Specificity / Q000187:drug effects / Q000502:physiology; D010047:Ovalbumin / Q000276:immunology; D010446:Peptide Fragments; D010447:Peptide Hydrolases; D046988:Proteasome Endopeptidase Complex; D011506:Proteins / Q000235:genetics / Q000378:metabolism; D012333:RNA, Messenger / Q000378:metabolism; D013601:T-Lymphocytes / Q000166:cytology / Q000276:immunology / Q000378:metabolism; D013602:T-Lymphocytes, Cytotoxic / Q000166:cytology / Q000276:immunology / Q000378:metabolism
D001324:Autoantigens; D004527:Egg Proteins; D000939:Epitopes; D016056:Immunodominant Epitopes; C099558:Ki antigen; D009097:Multienzyme Complexes; C110366:OVA-8; D010446:Peptide Fragments; D011506:Proteins; D012333:RNA, Messenger; D000255:Adenosine Triphosphate; D010047:Ovalbumin; D010447:Peptide Hydrolases; D003546:Cysteine Endopeptidases; D046988:Proteasome Endopeptidase Complex; C486213:Psme1 protein, mouse; C486214:Psme2 protein, mouse; D019746:Intramolecular Oxidoreductases; C042501:dopachrome isomerase