Role of SAM in Plasma Cell Differentiation and Function

Abstract

Abstract Plasma cells (PCs) are terminally differentiated B cells which secrete high levels of immunoglobulin (Ig). While Ig is essential for neutralizing and clearing pathogens, an excess of Ig is detrimental in autoimmune conditions. The transcription factor Blimp-1 is necessary and sufficient for this transition to PCs and is known to regulate Ig secretion. PC differentiation is reliant on multiple levels of regulation - epigenetic, post-transcriptional, and translational, which we hypothesize are dependent on methyltransferase activity for dynamic methylation. PCs also upregulate high levels of CD98, which functions as a membrane transporter for amino acids such as methionine, and thus initialization of the methionine cycle. In this cycle, methionine adenosyltransferase (MAT) coordinates the production of the methyl donor S-adenosylmethionine (SAM) from methionine. We are interested in determining whether this strong expression of CD98 is dependent on Blimp-1 or regulated by PCs, and to understand the role of SAM is this differentiation event. Utilizing a Blimp-1-YFP reporter mouse line, we are able to detect the transition to PCs in-vitro and study the requirement for SAM during this transition. Depletion of the precursor to SAM, methionine, resulted in a loss of PC number and secretory capacity. To specifically target the role of SAM for PCs, we treated in-vitro cultured PCs with inhibitors of MAT2A. Preliminary data provides evidence that inhibition of SAM reduces PC phenotype, function, and viability. We aim to determine the role of SAM in Ig secretion through transcriptional analysis and metabolomics, and hypothesize that Ig post-transcriptional regulation in PCs is controlled by methyltransferase activity.