Abstract
RNA splicing patterns in antibody-secreting cells are shaped by endoplasmic reticulum stress, ELL2 (eleven-nineteen lysine-rich leukemia gene 2) induction, and changes in the levels of snRNAs. Endoplasmic reticulum stress induces the unfolded protein response comprising a highly conserved set of genes crucial for cell survival; among these is Ire1, whose auto-phosphorylation drives it to acquire a regulated mRNA decay activity. The mRNA-modifying function of phosphorylated Ire1 non-canonically splices Xbp1 mRNA and yet degrades other cellular mRNAs with related motifs. Naïve splenic B cells will activate Ire1 phosphorylation early on after lipopolysaccharide (LPS) stimulation, within 18 h; large-scale changes in mRNA content and splicing patterns result. Inhibition of the mRNA-degradation function of Ire1 is correlated with further differences in the splicing patterns and a reduction in the mRNA factors for snRNA transcription. Some of the >4000 splicing changes seen at 18 h after LPS stimulation persist into the late stages of antibody secretion, up to 72 h. Meanwhile some early splicing changes are supplanted by new splicing changes introduced by the up-regulation of ELL2, a transcription elongation factor. ELL2 is necessary for immunoglobulin secretion and does this by changing mRNA processing patterns of immunoglobulin heavy chain and >5000 other genes.
Highlights
In the transition from naïve B lymphocytes to antibody-secreting cells, a characteristic morphological change is the appearance of a large amount of the endoplasmic reticulum (ER) along with the production of large quantities of the secreted form of the immunoglobulin (Ig) protein; these activated B cells can persist and secrete Ig for a long time [1,2]
All three pathways can be activated by factors that draw Grp78 away from its steady state location in the ER lumen where it is associated with Ire1, activating transcription factor 6 (Atf6), and Perk to become involved in chaperoning the folding of nascent proteins
When MIN6 cells are treated with thapsigargin (TG) a drug known to induce ER stress within 2 to 5 h of treatment in the absence of any insulin synthesis [34], Ire1 and regulated Ire1-dependent mRNA decay (RIDD) activation occur; there is an increase in the Xbp1 short/spliced RNA form, and ~five-fold CHOP (Ddit3) mRNA induction, all hallmarks of TG-induced stress [35]
Summary
In the transition from naïve B lymphocytes to antibody-secreting cells, a characteristic morphological change is the appearance of a large amount of the endoplasmic reticulum (ER) along with the production of large quantities of the secreted form of the immunoglobulin (Ig) protein; these activated B cells can persist and secrete Ig for a long time [1,2]. The UPR in many cells and across many phyla relies on three pathways: inositol-requiring enzyme (Ire1) and X-box protein (Xbp1); the activating transcription factor 6 (Atf6) pathway; and a third pathway involving the protein kinase R (PKR)-like endoplasmic reticulum kinase (Perk). All three pathways can be activated by factors that draw Grp away from its steady state location in the ER lumen where it is associated with Ire, Atf, and Perk to become involved in chaperoning the folding of nascent proteins. This allows Ire to auto-phosphorylate in the membrane and acquire the additional activities on RNAs described as regulated Ire1-dependent mRNA decay (RIDD). The role of ELL2, a transcription elongation factor, induced later in the B cell development pathway toward antibody-secreting cells in directing alternative RNA splicing, will be reviewed
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