IRE1α Kinase Activation Modes Control Alternate Endoribonuclease Outputs to Determine Divergent Cell Fates

By Dan Han, Alana G. Lerner, L. Walle, John-Paul Upton, Weihong Xu, Andrew R Hagen, B. J. Backes, Scott A Oakes, F. Papa. Cell, 2009

808 citations recorded by the source corpus.

SUMMARY During endoplasmic reticulum (ER) stress, homeostatic signaling through the unfolded protein response (UPR) augments ER protein-folding capacity. If homeostasis is not restored, the UPR triggers apoptosis. We found that the ER transmembrane kinase/endoribonuclease (RNase) IRE1α is a key component of this apoptotic switch ER stress induces IRE1α kinase autophosphorylation, activating the RNase to splice XBP1 mRNA and produce the homeostatic transcription factor, XBP1s. Under ER stress—or forced autophosphorylation—IRE1α’s RNase also causes endonucleolytic decay of many ER-localized mRNAs, including those encoding chaperones, as early events culminating in apoptosis. Using chemical-genetics, we show that kinase inhibitors bypass autophosphorylation to activate the RNase by an alternate mode that enforces XBP1 splicing, and averts mRNA decay and apoptosis. Alternate RNase activation by kinase-inhibited IRE1α can be reconstituted in vitro. We propose that divergent cell fates during ER stress hinge on a balance between IRE1α RNase outputs that can be tilted with kinase inhibitors to favor survival.

Subfields: Cell Biology, Molecular Biology, Surgery

View Paper: https://www.semanticscholar.org/paper/36764ffda300f8e923b9909cf7392ceac2dfc33b

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In Cell Biology

1. C. Hetz
2. R. Kaufman
3. Shiyu Wang
4. Peter Walter
5. F. Urano
6. H. Malhi
7. B. Gardner
8. C. M. Oslowski

In Molecular Biology

1. C. Hetz
2. R. Kaufman
3. Shiyu Wang
4. Peter Walter
5. H. Malhi
6. F. Urano
7. C. M. Oslowski
8. G. Hotamışlıgil

In Surgery

1. R. Kaufman
2. C. Hetz
3. Peter Walter
4. Shiyu Wang
5. F. Urano
6. C. M. Oslowski
7. J. Malhotra
8. G. Hotamışlıgil

Citations in the corpus

• Regulation of cytoplasmic mRNA decay (2012, neutral): “IRE1 also cleaves and destabilizes mRNAs encoding some of the proteins that transit through the endoplasmic reticulum (that is, membrane-bound and secreted proteins”
• Endoplasmic reticulum stress sensing in the unfolded protein response. (2013, background): “This pathway, termed Regulated Ire1-Depen- dent Decay (RIDD), cleaves mRNAs encoding membrane and secreted proteins and may consequently decrease the protein influx into the ER.”
• The unfolded protein response: controlling cell fate decisions under ER stress and beyond (2012, background): “In addition, the selective degradation of mRNA encoding for certain ER-located proteins is initiated through regulated IRE1-dependent decay ( RIDD”
• Endoplasmic Reticulum Stress and the Inflammatory Basis of Metabolic Disease (2010, neutral): “, 2006) and divergent effects of IRE1-mediated XBP1 splicing and IRE1a-triggered degradation of mRNAs localized in the ER may be critical determinants of the life and death outcomes resulting from ER stress (Han et al., 2009).”
• Endoplasmic Reticulum Stress in Liver Disease (2010, background): “The IRE1a RNase activity is also implicated in the degradation of several cellular mRNAs, a process named regulated IRE1-dependent decay (RIDD) [51–52], including proinsulin mRNA and IRE1a mRNA itself [42,131].”
• The C/EBP Homologous Protein (CHOP) Transcription Factor Functions in Endoplasmic Reticulum Stress-Induced Apoptosis and Microbial Infection (2019, background): “Unfolded proteins in the ER stimulate IRE1α oligomerization and autophosphorylation, which activates the endoribonuclease activity (41) .”
• The impact of the unfolded protein response on human disease (2012, background): “However, it was proposed that activated IRE1 degrades proinsulin mRNA to inhibit insulin production (Lipson et al., 2006; Han et al., 2009).”
• Measuring ER stress and the unfolded protein response using mammalian tissue culture system (2011, background): “In b cell lines, insulin mRNA has been shown to be a substrate of IRE1 and is quickly degraded under ER stress conditions (Han et al., 2009; Lipson et al., 2008; Pirot et al., 2007).”