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Allosteric inhibition of the IRE1α RNase preserves cell viability and function during endoplasmic reticulum stress.
Ghosh, Rajarshi; Wang, Likun; Wang, Eric S; Perera, B Gayani K; Igbaria, Aeid; Morita, Shuhei; Prado, Kris; Thamsen, Maike; Caswell, Deborah; Macias, Hector; Weiberth, Kurt F; Gliedt, Micah J; Alavi, Marcel V; Hari, Sanjay B; Mitra, Arinjay K; Bhhatarai, Barun; Schürer, Stephan C; Snapp, Erik L; Gould, Douglas B; German, Michael S; Backes, Bradley J; Maly, Dustin J; Oakes, Scott A; Papa, Feroz R.
Afiliación
  • Ghosh R; 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,
  • Wang L; 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
  • Wang ES; Department of Pathology, University of California, San Francisco, San Francisco, CA 94143, USA.
  • Perera BG; Department of Chemistry, University of Washington, Seattle, WA 98195, USA.
  • Igbaria A; 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
  • Morita S; 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
  • Prado K; 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
  • Thamsen M; 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
  • Caswell D; Department of Pathology, University of California, San Francisco, San Francisco, CA 94143, USA.
  • Macias H; 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.
  • Weiberth KF; 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
  • Gliedt MJ; 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.
  • Alavi MV; Department of Ophthalmology, University of California, San Francisco, San Francisco, CA 94143, USA.
  • Hari SB; Department of Chemistry, University of Washington, Seattle, WA 98195, USA.
  • Mitra AK; Department of Chemistry, University of Washington, Seattle, WA 98195, USA.
  • Bhhatarai B; Department of Molecular and Cellular Pharmacology,, Miller School of Medicine, University of Miami, FL 33136, USA.
  • Schürer SC; 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.
  • Snapp EL; Department of Anatomy and Structural Biology, Albert Einstein College of Medicine, Bronx, NY 10461, USA.
  • Gould DB; 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.
  • German MS; 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.
  • Backes BJ; 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.
  • Maly DJ; Department of Chemistry, University of Washington, Seattle, WA 98195, USA.
  • Oakes SA; 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.
  • Papa FR; 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
Cell ; 158(3): 534-48, 2014 Jul 31.
Article en En | MEDLINE | ID: mdl-25018104
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 ß 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.
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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Proteínas Serina-Treonina Quinasas / Inhibidores de Proteínas Quinasas / Endorribonucleasas / Estrés del Retículo Endoplásmico Tipo de estudio: Prognostic_studies Límite: Animals / Humans / Male Idioma: En Revista: Cell Año: 2014 Tipo del documento: Article
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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Proteínas Serina-Treonina Quinasas / Inhibidores de Proteínas Quinasas / Endorribonucleasas / Estrés del Retículo Endoplásmico Tipo de estudio: Prognostic_studies Límite: Animals / Humans / Male Idioma: En Revista: Cell Año: 2014 Tipo del documento: Article