プロテアソームの活性化因子PA28ファミリーの分子的性質とγ-インターフェロンによる調節機構

The proteasome is a large multicatalytic protease complex with an apparent sedimentation coefficient of 20S. It exists as a latent from in cells, being activated fully by the novel identified endogenous prtein, named proteasome activator PA28. The native PA28 is approximately 200 kDa protein, which binds directly to both ends of the cylindrical 20S proteasome to form a football-like complex. By recent cDNA cloning for two homologous PA28 proteins, called PA28α and PA28β, Ki antigen found previously as a nuclear protein detected with autoantibodies in human sera was identified as a structurally related third protein, but a relationship between Ki antigen and two PA28 proteins or the 20S proteasome is unknown. In the present study, we showed that Ki antigen belongs to a new member of the PA28 family proteins, because it was co-purified and co-sedimented with PA28α and PA28β, and because it was associated reversibly with the 20S proteasome, and thus Ki antigen was renamed as PA28α. Moreover, anti-PA28γ antibody did not precipitate immunologically with PA28α and PA28β, although the latter two proteins were co-immunoprecipitated by respective antibodies, suggesting that the complex containing PA28γ differs from that consisting of PA28α and PA28β. Recombinant PA28α expressed in E. coli activated greatly on the proteasomal peptidase activity solely, but PA28β and PA28γ did not reveal notable effects, although PA28β enhanced the PA28α-dependent activation observed only at the low concentration of PA28α without affecting the maximal activity. Intrigutingly, a major immunomodulatory cytokine γ-interferon (γ-IFN) induced almost complete loss of the PA28γ protein without affecting the mRNA level in cells, whereas the messages and proteins of both PA28α and PA28β were coordinately upregulated by γ-IFN. Thus, γ-IFN inducible PA28α and PA28β are assumed o play an important role for processing of endogeous antigens. Moreover, PA28γ may be involved in distinct biological processes from other two PA28 proteins, judging from their reciprocal expression in response to γ-IFN.