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

泛素蛋白酶体系统(UPS)和干扰素(IFN)都是蛋白酶体依赖的MHC-I类抗原处理和提呈过程中公认的参与者和调节者。我们最近的研究表明，IFN诱导新翻译的、短寿命的蛋白质快速和增强的多泛素化，随后瞬时积累多Ub-连接物。这些结合物的消除与26S免疫蛋白酶体的形成有关。类似地，我们证明了在DC成熟过程中多聚Ub结合物的积累。然而，这与26S蛋白酶体的减少和20S/PA28蛋白酶体复合体作为主要的胞浆蛋白水解酶的建立有关。本项目的目的是研究UPS相关酶在干扰素诱导的增强底物泛素化过程中的作用，对累积的Ub结合物池的质量和动力学进行表征，并研究累积的多Ub结合物对MHC I类抗原递呈的重要性。在人树突状细胞中，我们将首次研究内毒素诱导不同类型的多-Ub结合物聚集的作用和性质，并确定20S/PA28蛋白酶体复合体在DC功能和蛋白酶体依赖的交叉提呈中的作用。

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.