Mechanisms by which CIITA regulates the expression of MHC class II genes of the immune system.

The MHC class lI transactivator (CIITA) plays a central role in adaptive immune responses. CIITA directly controls the activation and expression of MHC class II genes, and can repress the expression of Th2 cytokine genes during Th1 cell differentiation. Although CIITA does not bind DNA, contacts with multifarious proteins allows CIITA to function. CIITA interaction with proteins that bind the MHC class II promoter, in combination with associations CIITA makes with constituents of the basal transcriptional machinery, are thought to orchestrate the formation of a functional enhanceosome complex required for expression of MHC class II genes. Interactions between CIITA and the co-activators p300/CBP lead to synergistic activation of MHC class II promoters and is one mechanism by which CIITA can repress IL-4 gene expression. Hence, the interaction CIITA makes with the co-activators p300/CBP has a different functional consequence dependent upon the gene in question. CIITA forms complexes with itself and these interactions are important for CIITA to function as a transactivator. A centrally located region of CIITA was shown to be sufficient and necessary for CIITA self-association as well as being capable of interacting with both the N- and C-terminal regions of the protein. We have identified CIITA as a phosphoprotein. Phosphorylation of CIITA by cAMP dependent protein kinase (PKA) modulates CIITA's transactivation potential. The presence of excess catalytic subunit of PKA induces the hyper-phosphorylation of CIITA and it is the hyper-phosphorylated form of CIITA which self-associates, complexes with DNA binding proteins and interacts with the co-activator p300/CBP. These interactions result in a large induction of MHC class II promoter activity. Finally, intra-molecular interactions between the C-terminal leucine rich repeat and the central portion of the protein appear to negatively regulate self-association and are dependent upon the phosphorylation status of the protein.Ph.D.Biological SciencesHealth and Environmental SciencesImmunologyMicrobiologyMolecular biologyUniversity of Michigan, Horace H. Rackham School of Graduate Studieshttp://deepblue.lib.umich.edu/bitstream/2027.42/128623/2/3029430.pd