Protective antibody responses depend upon secreted immunoglobulin. This is regulated in a stage-specific manner upon the differentiation of B cell blasts into plasma cells and depends on the upregulation of the Blimp-1 transcription factor. Blimp-1 orchestrates the plasma cell gene program that includes the regulation of genes important for secretion of large quantities of immunoglobulin, i.e. post-translational regulation. Blimp-1 is also necessary for post- transcriptional regulation of the immunoglobulin heavy chain primary transcript by somehow affecting the competing alternative splicing and alternative poly-adenylation reactions at play on this transcript. Using a structure-function approach, I had found a novel domain of Blimp-1, that exhibits a high degree of structural similarity to lysine-methyltransferase (SET) domains, to be essential for post-transcriptional regulation of the immunoglobulin primary transcript but not for post-translational regulation of immunoglobulin secretion. This proposal aims to elucidate the role of this domain in post-transcriptional regulation of the immunoglobulin transcript and perhaps other such regulated transcripts important for plasma cell biology. Furthermore, we will explore the possibility that methyltransferase activity of Blimp-1 plays a critical role in this process.
Although it is appreciated that Blimp-1 controls post-translational regulation of antibody secretion, how it controls antibody secretion at the post-transcriptional level is not understood. This application seeks to investigate this aspect of B cell and Blimp-1 biology as well as to explore whether it is associated with methyltransferase activity.
