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 German; Bradley J Backes; Dustin J Maly; Scott A Oakes; Feroz R Papa

doi:10.1016/j.cell.2014.07.002

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

Cell. 2014 Jul 31;158(3):534-48. doi: 10.1016/j.cell.2014.07.002. Epub 2014 Jul 10.

Authors

Rajarshi Ghosh¹, Likun Wang², Eric S Wang³, B Gayani K Perera⁴, Aeid Igbaria², Shuhei Morita², Kris Prado², Maike Thamsen², Deborah Caswell³, Hector Macias⁵, Kurt F Weiberth², Micah J Gliedt⁶, Marcel V Alavi⁷, Sanjay B Hari⁴, Arinjay K Mitra⁴, Barun Bhhatarai⁸, Stephan C Schürer⁹, Erik L Snapp¹⁰, Douglas B Gould¹¹, Michael S German⁵, Bradley J Backes⁶, Dustin J Maly⁴, Scott A Oakes¹², Feroz R Papa¹³

Affiliations

¹ Department of Medicine, University of California, San Francisco, San Francisco, CA 94143, USA; Department of Pathology, University of California, San Francisco, San Francisco, CA 94143, USA; Diabetes Center, University of California, San Francisco, San Francisco, CA 94143, USA; Lung Biology Center, University of California, San Francisco, San Francisco, CA 94143, USA; California Institute for Quantitative Biosciences, University of California, San Francisco, San Francisco, CA 94143, USA.
² Department of Medicine, University of California, San Francisco, San Francisco, CA 94143, USA; Diabetes Center, University of California, San Francisco, San Francisco, CA 94143, USA; Lung Biology Center, University of California, San Francisco, San Francisco, CA 94143, USA; California Institute for Quantitative Biosciences, University of California, San Francisco, San Francisco, CA 94143, USA.
³ Department of Pathology, University of California, San Francisco, San Francisco, CA 94143, USA.
⁴ Department of Chemistry, University of Washington, Seattle, WA 98195, USA.
⁵ Department of Medicine, University of California, San Francisco, San Francisco, CA 94143, USA; Diabetes Center, University of California, San Francisco, San Francisco, CA 94143, USA.
⁶ Department of Medicine, University of California, San Francisco, San Francisco, CA 94143, USA; Lung Biology Center, University of California, San Francisco, San Francisco, CA 94143, USA.
⁷ Department of Ophthalmology, University of California, San Francisco, San Francisco, CA 94143, USA.
⁸ Department of Molecular and Cellular Pharmacology,, Miller School of Medicine, University of Miami, FL 33136, USA.
⁹ Center for Computational Science, Miller School of Medicine, University of Miami, FL 33136, USA; Department of Molecular and Cellular Pharmacology,, Miller School of Medicine, University of Miami, FL 33136, USA.
¹⁰ Department of Anatomy and Structural Biology, Albert Einstein College of Medicine, Bronx, NY 10461, USA.
¹¹ Department of Ophthalmology, University of California, San Francisco, San Francisco, CA 94143, USA; Department of Anatomy, University of California, San Francisco, San Francisco, CA 94143, USA.
¹² Department of Pathology, University of California, San Francisco, San Francisco, CA 94143, USA; Diabetes Center, University of California, San Francisco, San Francisco, CA 94143, USA. Electronic address: [email protected].
¹³ Department of Medicine, University of California, San Francisco, San Francisco, CA 94143, USA; Diabetes Center, University of California, San Francisco, San Francisco, CA 94143, USA; Lung Biology Center, University of California, San Francisco, San Francisco, CA 94143, USA; California Institute for Quantitative Biosciences, University of California, San Francisco, San Francisco, CA 94143, USA. Electronic address: [email protected].

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.

Publication types

Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't
Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

Allosteric Regulation
Animals
Apoptosis / drug effects
Cell Line
Endoplasmic Reticulum Stress*
Endoribonucleases / antagonists & inhibitors*
Endoribonucleases / chemistry
Endoribonucleases / metabolism
Enzyme Activation / drug effects
Humans
Islets of Langerhans / metabolism
Male
Mice
Protein Kinase Inhibitors / pharmacology*
Protein Serine-Threonine Kinases / antagonists & inhibitors*
Protein Serine-Threonine Kinases / chemistry
Protein Serine-Threonine Kinases / metabolism
Rats
Retina / metabolism
Ribonucleases / antagonists & inhibitors

Substances

Protein Kinase Inhibitors
ERN1 protein, human
Ern1 protein, mouse
Protein Serine-Threonine Kinases
Endoribonucleases
Ribonucleases

Abstract

Publication types

MeSH terms

Substances

Grants and funding