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Int. J. Mol. Sci. 2018, 19(12), 3919; https://doi.org/10.3390/ijms19123919

Linking Endoplasmic Reticular Stress and Alternative Splicing

School of Medicine, Department of Immunology, University of Pittsburgh, E1059 Biomedical Science Tower, Pittsburgh, PA 15261, USA
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Received: 16 November 2018 / Revised: 4 December 2018 / Accepted: 5 December 2018 / Published: 7 December 2018
(This article belongs to the Special Issue Endoplasmic Reticulum Stress and Unfolded Protein Response)
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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. View Full-Text
Keywords: B cells; RNA splicing; ER stress; unfolded protein response; RIDD B cells; RNA splicing; ER stress; unfolded protein response; RIDD
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Carew, N.T.; Nelson, A.M.; Liang, Z.; Smith, S.M.; Milcarek, C. Linking Endoplasmic Reticular Stress and Alternative Splicing. Int. J. Mol. Sci. 2018, 19, 3919.

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