title: Allosteric inhibition of the IRE1α RNase preserves cell viability and function during endoplasmic reticulum stress.
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.
authors.affiliation: 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.
authors.forename: Rajarshi
authors.initials: R
authors.lastname: Ghosh
authors.affiliation: 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.
authors.forename: Likun
authors.initials: L
authors.lastname: Wang
authors.affiliation: Department of Pathology, University of California, San Francisco, San Francisco, CA 94143, USA.
authors.forename: Eric S
authors.initials: ES
authors.lastname: Wang
authors.affiliation: Department of Chemistry, University of Washington, Seattle, WA 98195, USA.
authors.forename: B Gayani K
authors.initials: BG
authors.lastname: Perera
authors.affiliation: 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.
authors.forename: Aeid
authors.initials: A
authors.lastname: Igbaria
authors.affiliation: 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.
authors.forename: Shuhei
authors.initials: S
authors.lastname: Morita
authors.affiliation: 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.
authors.forename: Kris
authors.initials: K
authors.lastname: Prado
authors.affiliation: 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.
authors.forename: Maike
authors.initials: M
authors.lastname: Thamsen
authors.affiliation: Department of Pathology, University of California, San Francisco, San Francisco, CA 94143, USA.
authors.forename: Deborah
authors.initials: D
authors.lastname: Caswell
authors.affiliation: 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.
authors.forename: Hector
authors.initials: H
authors.lastname: Macias
authors.affiliation: 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.
authors.forename: Kurt F
authors.initials: KF
authors.lastname: Weiberth
authors.affiliation: 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.
authors.forename: Micah J
authors.initials: MJ
authors.lastname: Gliedt
authors.affiliation: Department of Ophthalmology, University of California, San Francisco, San Francisco, CA 94143, USA.
authors.forename: Marcel V
authors.initials: MV
authors.lastname: Alavi
authors.affiliation: Department of Chemistry, University of Washington, Seattle, WA 98195, USA.
authors.forename: Sanjay B
authors.initials: SB
authors.lastname: Hari
authors.affiliation: Department of Chemistry, University of Washington, Seattle, WA 98195, USA.
authors.forename: Arinjay K
authors.initials: AK
authors.lastname: Mitra
authors.affiliation: Department of Molecular and Cellular Pharmacology,, Miller School of Medicine, University of Miami, FL 33136, USA.
authors.forename: Barun
authors.initials: B
authors.lastname: Bhhatarai
authors.affiliation: 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.
authors.forename: Stephan C
authors.initials: SC
authors.lastname: Schürer
authors.affiliation: Department of Anatomy and Structural Biology, Albert Einstein College of Medicine, Bronx, NY 10461, USA.
authors.forename: Erik L
authors.initials: EL
authors.lastname: Snapp
authors.affiliation: 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.
authors.forename: Douglas B
authors.initials: DB
authors.lastname: Gould
authors.affiliation: 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.
authors.forename: Michael S
authors.initials: MS
authors.lastname: German
authors.affiliation: 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.
authors.forename: Bradley J
authors.initials: BJ
authors.lastname: Backes
authors.affiliation: Department of Chemistry, University of Washington, Seattle, WA 98195, USA.
authors.forename: Dustin J
authors.initials: DJ
authors.lastname: Maly
authors.affiliation: 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: scott.oakes@ucsf.edu.
authors.forename: Scott A
authors.initials: SA
authors.lastname: Oakes
authors.affiliation: 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: frpapa@medicine.ucsf.edu.
authors.forename: Feroz R
authors.initials: FR
authors.lastname: Papa
mesh_terms: D000494:Allosteric Regulation; D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D002460:Cell Line; D059865:Endoplasmic Reticulum Stress; D004722:Endoribonucleases / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000378:metabolism; D004789:Enzyme Activation / Q000187:drug effects; D006801:Humans; D007515:Islets of Langerhans / Q000378:metabolism; D008297:Male; D051379:Mice; D047428:Protein Kinase Inhibitors / Q000494:pharmacology*; D017346:Protein Serine-Threonine Kinases / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000378:metabolism; D051381:Rats; D012160:Retina / Q000378:metabolism; D012260:Ribonucleases / Q000037:antagonists & inhibitors
chemical_list: D047428:Protein Kinase Inhibitors; C528229:ERN1 protein, human; C510185:Ern1 protein, mouse; D017346:Protein Serine-Threonine Kinases; D004722:Endoribonucleases; D012260:Ribonucleases