Project description:Antibody secreting cells (ASCs) survive in niche microenvironments as mature plasma cells, but how niche signals are integrated is poorly understood. Here we dissect such a response in human ASCs using an in vitro model, time course expression data, and a parsimonious gene correlation networking approach (PGCNA), we map expression changes that occur during the maturation to quiescent PCs. We demonstrate that TGF-beta, a niche factor, drives a focused effect on gene expression, including up-regulation of CXCR4, while progression to secretory optimization is completed. Heightened expression of CXCR4 in the presence of TGF-beta is in turn associated with enhanced ERK activation in response to SDF1. Mapping expression changes following SDF1/TGF-beta signaling we identify a module of immediate early genes including EGR1 as a primary nexus, upstream of subsequent waves of gene expression including genes encoding membrane proteins, such as solute channels and surface receptors. We conclude that niche signals delivered from SDF1 and TGFB integrate at the level of MAPkinase pathway and link downstream to changes in potential capacity for further niche sensing.proteases (MBTPS2/S2P) and release of the cytoplasmic domain as an active transcription factor. Such regulation is shared with a family of CREB3-related transcription factors and sterol regulatory element-binding proteins (SREBPs). Of these, we identify that the CREB3 family member CREB3L2 is strongly induced and activated during the transition from B-cell to plasma cell state. Inhibition of site-1 protease leads to a profound reduction in plasmablast number linked to induction of autophagy. Plasmablasts generated in the presence of site-1 protease inhibitor segregated into CD38high and CD38low populations, the latter characterized by a marked reduction in the capacity to secrete IgG. Site-1 protease inhibition is accompanied by a distinctive change in gene expression associated with amino acid synthesis, steroid and fatty acid synthesis pathways. These result demonstrate that transcriptional control of metabolic programs necessary for secretory activity can be targeted via site-1 protease inhibition during ASC differentiation.

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EGR1 and the MAPKinase pathway provide a focus for signal integration in antibody secreting cells

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