@article{74de0e27e8434e33ba97a5422d73f3b0,
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.",
author = "Rajarshi Ghosh and Likun Wang and Wang, {Eric S.} and Perera, {B. Gayani K.} and Aeid Igbaria and Shuhei Morita and Kris Prado and Maike Thamsen and Deborah Caswell and Hector Macias and Weiberth, {Kurt F.} and Gliedt, {Micah J.} and Alavi, {Marcel V.} and Hari, {Sanjay B.} and Mitra, {Arinjay K.} and Barun Bhhatarai and Sch{\"u}rer, {Stephan C.} and Snapp, {Erik L.} and Gould, {Douglas B.} and German, {Michael S.} and Backes, {Bradley J.} and Maly, {Dustin J.} and Oakes, {Scott A.} and Papa, {Feroz R.}",
note = "Funding Information: We thank Michael Matthes and Doug Yasumura for technical assistance with rat models, Vinh Nguyen for islet isolation, and Oakes and Papa lab members for discussions. The work was supported by National Institutes of Health grants DP2OD001925 (F.R.P.), RO1 CA136577 (S.A.O.), RO1 DK080955 (F.R.P.), RO1 DK095306 (S.A.O. and F.R.P.), RO1 DK100623 (D.J.M. and F.R.P.), PO1 HL108794 (F.R.P.), P30 DK063720 (F.R.P. and M.S.G.), UO1 DK089541 (F.R.P. and M.S.G.), RO1 DK021344 (M.S.G.), RO1 GM086858 (D.J.M.), R21 CA177402 (D.J.M.), EY019504 (D.B.G.), EY01919 (D.B.G.), EY06842 (D.B.G.), and F31-NS083323 (E.S.W.); HHMI Physician-Scientist Early Career Award (S.A.O.); American Cancer Society Research Scholar Award (S.A.O.); Burroughs Wellcome Foundation (F.R.P.); Juvenile Diabetes Research Foundation (F.R.P. and S.A.O.); Harrington Discovery Institute Scholar-Innovator Award (S.A.O. and F.R.P.); Alfred P. Sloan Foundation (D.J.M.); Camille and Henry Dreyfus Foundation (D.J.M.); National Science Foundation (E.S.W.); and American Diabetes Association ADA-7-07-MN-22 (H.M.S.). ",
year = "2014",
month = jul,
day = "31",
doi = "10.1016/j.cell.2014.07.002",
language = "English",
volume = "158",
pages = "534--548",
journal = "Cell",
issn = "0092-8674",
publisher = "Cell Press",
number = "3",
}
