The author describe the first real PA28ab double-knockout mouse and present experimental evidence that PA28 is essential for the generation of a specific epitope in vivo.
Immunoproteasome assembly and antigen presentation in mice lacking both PA28α and PA28β
Murata, S., Udono, H,, Tanahashi, N., Hamada, N,, Watanabe, K,, Adachi, K,, Yamano, T., Yui, K., Kobayashi, N., Kasahara, M., Tanaka, K. & Chiba, T.
These two reports provide compelling evidence against the dogma that antigenic peptides were products of protein-turn over. Most peptides were in fact derived from newly synthesized proteins.
Rapid degradation of a large fraction of newly synthesized proteins by proteasomes
The first report that describes an IFN-γ independent inducible system for immunoproteasome formation and shows that only low amounts of immunoproteaomes are needed for an effective immune response.
MHC class I antigen processing of an adenovirus CTL epitope is linked to the levels of immunoproteasomes in infected cells
Sijts, A, Standera, S., Beekmann, N., van Veelen, P.A., Ossendorp, F.A., Melief, C.J. & Kloetzel, P.M.
This study presents evidence that proteasomes may not function in a completely processive way. The authors also discuss the possibility that 20S proteasomes take up substrates that are cut down to size by aminopeptidases.
Lysozyme degradation by the bovine multicatalytic proteinase complex (proteasome): evidence for a nonprocessive mode of degradation
Wang, R., Chait, B.T., Wolf, I., Kohanski, R.A. & Cardozo, C.
This study show that there are at least two distinct proteolytic steps involved in the generation of a MHC class I—presented peptide in living cells. Proteasomes are needed to make initial cleavages in an antigen and are the only protease in living cells that could generate the proper C terminus of a presented peptide. A second proteolytic step trims extra residues from the N terminus of precursors to generate the mature presented peptide.
Two distinct proteolytic processes in the generation of a major histocompatibility complex class I-presented peptide
Incorporation of major histocompatibility complex encoded subunits LMP2 and LMP7 changes the quality of the 20S proteasome polypeptide processing products independent of interferon-γ
Kuckelkorn, U., Frentzel, S., Kraft, R., Kostka, S., Groettrup, M. & Kloetzel, P.M.
The first report implicating the proteasome as a generator of antigenic peptides. This study identified proteasome inhibitors and demonstrated that they block the degradation of most cell proteins and also the production of most MHC class I presented peptides. In contrast, these agents did not block the presentation of mature peptides injected or expressed in the cytosol of cells. These findings demonstrate that the majority of MHC class I—presented peptides are generated by the proteasomes.
Inhibitors of the proteasome block the degradation of most cell proteins and the generation of peptides presented on MHC class I molecules
Rock, K.L., Gramm, C., Rothstein, L., Clark, K., Stein, R., Dick, L., Hwang, D. & Goldberg, A.L.
The authors show for the first time that 20S proteasomes have the potential to generate epitopes in vitro and that immunoproteasomes exhibit an altered cleavage site preference.
IFN-γ stimulation modulates the proteolytic activity and cleavage site preference of 20S mouse proteasomes
These two papers reported that the MHC-encoded proteasomal subunits altered the peptidase activity of the proteasome. These findings provided the first evidence that these subunits helped to form the active sites of the proteolytic complex and altered how cleavages would be made in substrates.
γ-interferon and expression of MHC genes regulate peptide hydrolysis by proteasomes
This study showed that proteasomes incorporate two additional subunits encoded in the MHC class II region in the presence of interferon-γ (IFN-γ). This complex was eventually renamed the immunoproteasomes. This observation provided circumstantial evidence for a connection between proteasomes and the immune system. The involvement of the 'MHC-encoded' subunits and of the immune function of the proteasome was unknown.
Structural and serological similarity of MHC-linked LMP and proteasome (multicatalytic proteinase) complexes
First paper studying the mechanism of antigen generation and peptide loading of MHC class I molecules. The authors showed that the proteasome is somehow involved in this process.
Defective presentation to class I-restricted cytotoxic T lymphocytes in vaccinia-infected cells is overcome by enhanced degradation of antigen
Townsend, A., Bastin, J., Gould, K., Brownlee, G., Andrew, M., Coupar, B., Boyle, D., Chan, S. & Smith, G.
