IRE1-mediated unconventional mRNA splicing and S2P-mediated ATF6 cleavage merge to regulate XBP1 in signaling the unfolded protein response.

By Kyungho Lee, W. Tirasophon, Xiaohua Shen, M. Michalak, R. Prywes, T. Okada, Hiderou Yoshida, K. Mori, R. Kaufman. Genes & Development, 2002

1,073 citations recorded by the source corpus.

All eukaryotic cells respond to the accumulation of unfolded proteins in the endoplasmic reticulum (ER) by signaling an adaptive pathway termed the unfolded protein response (UPR). In yeast, a type-I ER transmembrane protein kinase, Ire1p, is the proximal sensor of unfolded proteins in the ER lumen that initiates an unconventional splicing reaction on HAC1 mRNA. Hac1p is a transcription factor required for induction of UPR genes. In higher eukaryotic cells, the UPR also induces site-2 protease (S2P)-mediated cleavage of ER-localized ATF6 to generate an N-terminal fragment that activates transcription of UPR genes. To elucidate the requirements for IRE1alpha and ATF6 for signaling the mammalian UPR, we identified a UPR reporter gene that was defective for induction in IRE1alpha-null mouse embryonic fibroblasts and S2P-deficient Chinese hamster ovary (CHO) cells. We show that the endoribonuclease activity of IRE1alpha is required to splice XBP1 (X-box binding protein) mRNA to generate a new C terminus, thereby converting it into a potent UPR transcriptional activator. IRE1alpha was not required for ATF6 cleavage, nuclear translocation, or transcriptional activation. However, ATF6 cleavage was required for IRE1alpha-dependent induction of UPR transcription. We propose that nuclear-localized IRE1alpha and cytoplasmic-localized ATF6 signaling pathways merge through regulation of XBP1 activity to induce downstream gene expression. Whereas ATF6 increases the amount of XBP1 mRNA, IRE1alpha removes an unconventional 26-nucleotide intron that increases XBP1 transactivation potential. Both processing of ATF6 and IRE1alpha-mediated splicing of XBP1 mRNA are required for full activation of the UPR.

Subfields: Biotechnology, Cell Biology, Molecular Biology

View Paper: https://www.semanticscholar.org/paper/463803e798d1dc4c5be87280b775ab551e05729e

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In Biotechnology

1. R. Kaufman
2. C. Hetz
3. D. Ron
4. J. Malhotra
5. M. Pagliassotti
6. Dong Wang
7. Yuren Wei
8. F. Topczewski

In Cell Biology

1. R. Kaufman
2. G. Hotamışlıgil
3. C. Hetz
4. J. Malhotra
5. Laurie H. Glimcher
6. D. Ron
7. Peter Walter
8. M. Schröder

In Molecular Biology

1. R. Kaufman
2. G. Hotamışlıgil
3. C. Hetz
4. Laurie H. Glimcher
5. D. Ron
6. J. Malhotra
7. M. Schröder
8. Ann-Hwee Lee

Citations in the corpus

• Roles of CHOP/GADD153 in endoplasmic reticulum stress (2004, background): “Ire1a / and XBP-1 / mice, which can induce ER chaperones upon ER stress, are embryonic lethal.(18,40,66) XBP-1 / livers show hypoplasia with numerous apoptotic hepatocytes, and XBP-1 / B cells fail to differentiate to plasma cells.”
• Adaptation to ER Stress Is Mediated by Differential Stabilities of Pro-Survival and Pro-Apoptotic mRNAs and Proteins (2006, background): “mRNA is low, and is itself up-regulated by UPR activation [”
• The unfolded protein response: controlling cell fate decisions under ER stress and beyond (2012, background): “Active IRE1α processes the mRNA encoding the transcription factor X box-binding protein 1 (XBP1), excising a 26-nucleotide-long intron that shifts the coding reading frame of this mRN”
• The endoplasmic reticulum stress response in immunity and autoimmunity (2008, background): “The IRE1 axis is the most evolutionarily conserved of the UPR branches and includes X-box-binding protein 1 ( XBP1 ), which is a homologue of HAC”
• ER stress regulation of ATF6 localization by dissociation of BiP/GRP78 binding and unmasking of Golgi localization signals. (2002, methodology): “The three ER also involved in the induction of mammalian ER stress- regulated genes (Harding et al., 2000; Lee et al., 2002;stress transducers that are regulated by BiP, ATF6, IRE1, and PERK all have ER luminal sensor and cytosolic ef- Yoshida et al., 2001).”
• Plasma cell differentiation and the unfolded protein response intersect at the transcription factor XBP-1 (2003, background): “Only spliced XBP-1 can reconstitute Ig secretion in Xbp1 −/− B cells and only spliced XBP-1 is a potent transcriptional activator for ER chaperone gene”
• The endoplasmic reticulum: structure, function and response to cellular signaling (2015, background): “First, ER-resident IRE1, a transmembrane endoribonuclease, mediates the post-transcriptional, non-canonical splicing of XBP1 mRNA that is localized to the ER [157–159] and encodes a transcription factor involved in upregulating additional stress response genes.”