Abstract
The unfolded protein response (UPR) and activation of XBP1 is necessary for high secretory efficiency and functional differentiation of antibody secreting cells (ASCs). The UPR additionally includes a branch in which membrane-bound transcription factors, exemplified by ATF6, undergo intramembrane-proteolysis by the sequential action of site-1 (MBTPS1/S1P) and site-2 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, steroid and fatty acid synthesis pathways. These results demonstrate that transcriptional control of metabolic programs necessary for secretory activity can be targeted via site-1 protease inhibition during ASC differentiation.
Highlights
During terminal differentiation of B-cells to plasma cells (PCs), specific gene expression programs are instigated to allow adaptation to the secretion of large amounts of immunoglobulin
We describe the progressive accumulation of CREB3L2 during PC differentiation and utilize the selective S1P inhibitor PF-429242 to establish that S1P-regulated events are essential for efficient antibody secreting cells (ASCs) differentiation and regulation of genes involved in the metabolic pathways necessary for adaptation to antibody secretion
In a detailed characterization of gene expression spanning multiple stages of human PC differentiation, CREB3L2 was identified as one of the genes mostly strongly induced in PCs, distinct from other CREB3 family members[15]
Summary
During terminal differentiation of B-cells to plasma cells (PCs), specific gene expression programs are instigated to allow adaptation to the secretion of large amounts of immunoglobulin. The available evidence suggests that B-cells utilize the UPR in an unconventional fashion[10], and other components of the ER stress response may provide partially redundant regulation of the secretory apparatus during PC differentiation Amongst these the CREB family has not been explored in the context of B-cell differentiation. CREB3L2 and other CREB3 family members share their mechanism of activation with ATF6 and sterol regulatory element binding protein, SREBP, a major transcriptional regulator of sterol and lipid synthesis. All of these factors are released from the ER, following appropriate stimulation, and migrate to the Golgi where they are cleaved by the sequential action of S1P and S2P11,13. This pathway reinforces the direct link between the secretory apparatus and the establishment of ASC state
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