Allosteric inhibition of the IRE1α RNase preserves cell viability and function during endoplasmic reticulum stress

Rajarshi Ghosh, Likun Wang, Eric S. Wang, B. Gayani K. Perera, Aeid Igbaria, Shuhei Morita, Kris Prado, Maike Thamsen, Deborah Caswell, Hector Macias, Kurt F. Weiberth, Micah J. Gliedt, Marcel V. Alavi, Sanjay B. Hari, Arinjay K. Mitra, Barun Bhhatarai, Stephan C. Schürer, Erik L. Snapp, Douglas B. Gould, Michael S. GermanBradley J. Backes, Dustin J. Maly, Scott A. Oakes, Feroz R. Papa

Research output: Contribution to journalArticle

198 Scopus citations

Abstract

Depending on endoplasmic reticulum (ER) stress levels, the ER transmembrane multidomain protein IRE1α promotes either adaptation or apoptosis. Unfolded ER proteins cause IRE1α lumenal domain homo-oligomerization, inducing trans autophosphorylation that further drives homo-oligomerization of its cytosolic kinase/endoribonuclease (RNase) domains to activate mRNA splicing of adaptive XBP1 transcription factor. However, under high/chronic ER stress, IRE1α surpasses an oligomerization threshold that expands RNase substrate repertoire to many ER-localized mRNAs, leading to apoptosis. To modulate these effects, we developed ATP-competitive IRE1α Kinase-Inhibiting RNase Attenuators - KIRAs - that allosterically inhibit IRE1α's RNase by breaking oligomers. One optimized KIRA, KIRA6, inhibits IRE1α in vivo and promotes cell survival under ER stress. Intravitreally, KIRA6 preserves photoreceptor functional viability in rat models of ER stress-induced retinal degeneration. Systemically, KIRA6 preserves pancreatic β cells, increases insulin, and reduces hyperglycemia in Akita diabetic mice. Thus, IRE1α powerfully controls cell fate but can itself be controlled with small molecules to reduce cell degeneration.

Original languageEnglish (US)
Pages (from-to)534-548
Number of pages15
JournalCell
Volume158
Issue number3
DOIs
StatePublished - Jul 31 2014

ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)

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    Ghosh, R., Wang, L., Wang, E. S., Perera, B. G. K., Igbaria, A., Morita, S., Prado, K., Thamsen, M., Caswell, D., Macias, H., Weiberth, K. F., Gliedt, M. J., Alavi, M. V., Hari, S. B., Mitra, A. K., Bhhatarai, B., Schürer, S. C., Snapp, E. L., Gould, D. B., ... Papa, F. R. (2014). Allosteric inhibition of the IRE1α RNase preserves cell viability and function during endoplasmic reticulum stress. Cell, 158(3), 534-548. https://doi.org/10.1016/j.cell.2014.07.002