Immunoproteasome assembly and antigen presentation in mice lacking both PA28α and PA28β

Two members of the proteasome activator, PA28α and PA28β, form a heteropolymer that binds to both ends of the 20S proteasome. Evidence in vitro indicates that this interferon-γ (IFN-γ)-inducible heteropolymer is involved in the processing of intracellular antigens, but its functions in vivo remain elusive. To investigate the role of PA28α/β in vivo, we generated mice deficient in both PA28α and PA28β genes. The ATP-dependent proteolytic activities were decreased in PA28α(–/–)/β(–/–) cells, suggesting that ‘hybrid proteasomes’ are involved in protein degradation. Treatment of PA28α(–/–)/β(–/–) cells with IFN-γ resulted in sufficient induction of the ‘immunoproteasome’. Moreover, splenocytes from PA28α(–/–)/β(–/–) 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 PA28β(–/–) mice. PA28α(–/–)/β(–/–) 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, PA28α/β is not a prerequisite for antigen presentation in general, but plays an essential role for the processing of certain antigens.