Untersuchungen zur Rolle der Tripeptidylpeptidase II-vermittelten Proteolyse invivo (In vivo-Role of Tripeptidyl Peptidase II-Mediated Proteolysis in Murine Cells and Mice)

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Whereas some groups favor that proteasomes only generate the C-termini of cytotoxic T-lymphocyte (CTL) epitopes (Craiu et al., 1997; Beninga et al., 1998), our work has suggested that they cleave precisely at both ends of many epitopes. We intend to use as substrate HIV-1-Nef, which contains at least 45 CTL epitopes, for digestion by isolated 20S, 26S and immunoproteasomes and to determine all degradation products. This will allow us to clarify the role of proteasomes in epitope generation, to better define the specificity of the various types of proteasomes (the specificities of 26S and immunoproteasomes have so far not been investigated systematically) and to develop algorithms for the prediction of proteasomal cleavage sites.Upregulation of TPPII, a cytosolic protease complex larger than the 26S proteasome, in proteasome inhibitor-adapted cells permits cell survival. We intend to investigate whether TPPII normally functions in cytosolic proteolysis down-stream of proteasomes and therefore is the eukaryotic pendant of the archaeal Tricorn protease. Further, we intend to analyze the adapted cells in more detail regarding impairment of proteasome functions and precise mechanisms by which TPPII permits survival.