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Publication Abstract from PubMed

The unfolded protein response (UPR) homeostatically matches endoplasmic reticulum (ER) protein-folding capacity to cellular secretory needs. However, under high or chronic ER stress, the UPR triggers apoptosis. This cell fate dichotomy is promoted by differential activation of the ER transmembrane kinase/endoribonuclease (RNase) IRE1alpha. We previously found that the RNase of IRE1alpha can be either fully activated or inactivated by ATP-competitive kinase inhibitors. Here we developed kinase inhibitors, partial antagonists of IRE1alpha RNase (PAIRs), that partially antagonize the IRE1alpha RNase at full occupancy. Biochemical and structural studies show that PAIRs promote partial RNase antagonism by intermediately displacing the helix alphaC in the IRE1alpha kinase domain. In insulin-producing beta-cells, PAIRs permit adaptive splicing of Xbp1 mRNA while quelling destructive ER mRNA endonucleolytic decay and apoptosis. By preserving Xbp1 mRNA splicing, PAIRs allow B cells to differentiate into immunoglobulin-producing plasma cells. Thus, an intermediate RNase-inhibitory 'sweet spot', achieved by PAIR-bound IRE1alpha, captures a desirable conformation for drugging this master UPR sensor/effector.

ATP-competitive partial antagonists of the IRE1alpha RNase segregate outputs of the UPR.,Feldman HC, Ghosh R, Auyeung VC, Mueller JL, Kim JH, Potter ZE, Vidadala VN, Perera BGK, Olivier A, Backes BJ, Zikherman J, Papa FR, Maly DJ Nat Chem Biol. 2021 Nov;17(11):1148-1156. doi: 10.1038/s41589-021-00852-0. Epub, 2021 Sep 23. PMID:34556859^[4]

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.