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Unfolded Protein Response-Dependent Communication and Contact among Endoplasmic Reticulum, Mitochondria, and Plasma Membrane

Linking Endoplasmic Reticular Stress and Alternative Splicing

School of Medicine, Department of Immunology, University of Pittsburgh, E1059 Biomedical Science Tower, Pittsburgh, PA 15261, USA
Author to whom correspondence should be addressed.
Int. J. Mol. Sci. 2018, 19(12), 3919;
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)
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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MDPI and ACS Style

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.

AMA Style

Carew NT, Nelson AM, Liang Z, Smith SM, Milcarek C. Linking Endoplasmic Reticular Stress and Alternative Splicing. International Journal of Molecular Sciences. 2018; 19(12):3919.

Chicago/Turabian Style

Carew, Nolan T., Ashley M. Nelson, Zhitao Liang, Sage M. Smith, and Christine Milcarek. 2018. "Linking Endoplasmic Reticular Stress and Alternative Splicing" International Journal of Molecular Sciences 19, no. 12: 3919.

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