The function of the Ubiquitin-Proteasome-System (UPS) in MHC class I antigen processing in target cells and maturing human dendritic cells (hDCs).

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Both the Ubiquitin-Proteasome-System (UPS) and interferons (IFNs) are established players and regulators in proteasome dependent MHC class I antigen processing and presentation. Our recent studies demonstrated that IFNs induce rapid and enhanced poly-ubiquitylation of newly translated, short lived proteins, followed by transient accumulation of poly-Ub-conjugates. The elimination of these conjugates is associated with 26S immunoproteasome formation. Similarly, we demonstrated an accumulation of poly-Ub-conjugates during DC maturation. This however is associated with a decrease in 26S proteasomes and the establishment of 20S/PA28 proteasome complexes as the predominant cytosolic protease. The aim of this project is to investigate the role of UPS related enzymes responsible for IFN induced enhanced substrate ubiquitylation, characterize the pool of accumulated Ub-conjugates with regard to their quality and dynamics and to study the importance of accumulated poly-Ub-conjugates for MHC class I antigen presentation. In human DCs we shall study for the first time the role and quality of LPS induced accumulation of the different types of poly-Ub-conjugates and determine the role of 20S/PA28 proteasome complexes in DC function and proteasome dependent cross presentation.