MHC Class II Transactivator Function & Regulation

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DESCRIPTION (provided by applicant): MHC class II transactivator (CIITA) is a critical transcription factor regulating the expression of genes that are vital to immune responses and for the establishment of normal immune homeostatic controls of a host. CIITA activates the expression of genes involved in antigen presentation but represses the expression of Th2 type cytokine and FasL. We and others have demonstrated that the activity of CIITA as an activator and a repressor is mediated by CIITA interaction with histone acetyltransferase CBP/p300. Recently, we and others also observed that CIITA forms a complex with self. CIITA mutants defective in self-association failed to activate the MHC class II promoter suggesting that the ability of self-association is linked to transactivation potential of CIITA. Therefore, understanding how CIITA activity is regulated by multiple interactions has great relevance towards understanding how immune response is modulated by CIITA. In the current application, we propose experiments with the overall objective of understanding the structure and function of CIITA to regulate the target gene expression. First, the mechanisms by which inter- and intra molecular interaction of CIITA is controlled and this information to activate CIITA function as a transcriptional regulator, will be explored through genetic, biochemical and molecular biology approaches. Secondly, the mechanisms whereby cells retain CIITA protein in an active and/or inactive form and respond to a signal to regulate CIITA activity by phosphorylation, will be investigated. Thirdly, we will examine CIITA interaction in living cells using fluorescence resonance energy transfer. The experiments described in this application will provide insight into how CIITA senses and responds to stimulus that occur during immune response, and disease states, to maintain cellular regulation.