Regulation of MHC class II genes and molecules

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My research program is focused on fundamental molecular mechanisms controlling the expression of Major histocompatibility class II (MHC-II) genes and the intracellular transport of MHC-II molecules. MHC-II molecules serve as antigen presenting molecules for CD4-positive T cells, which play a central role for the adaptive immune response, since they modulate most of the immune reactions, such as activation of B cell, macrophages and CD8-positive cytotoxic T cells. Both MHC-II genes and molecules are subject to multiple levels of control, which are essential for the correct function of the immune response and thus present a very interesting and relevant model system for the study of multi-layered regulatory circuits. The majority of positive and negative regulatory mechanisms of MHC-II gene expression are orchestrated directly or indirectly by the MHC-II transactivator CIITA. CIITA is a large non-DNA-binding transcriptional activator and its mode of action is only partially understood. We have found recently that the extreme N-terminal end of CIITA is both necessary for degradation and transcriptional activation. I propose to identify and characterize ubiquitin ligases involved in the N-terminal turnover of CIITA and other CIITA-associated proteins via a proteomic approach. Mechanisms involved in CIITA turnover and MHC-II gene activation will be analyzed in a time-resolved kinetic experiments. MARCH protein ubiquitin ligases have emerged as a novel class of immunomodulators. We have shown recently that MARCH1 is essential for the IL-10-induced down-regulation of MHC-II molecules expression in monocytes. The mode of action of MARCH proteins and their regulation is still only very poorly understood. I propose to study the regulation of the MARCH1 gene.