Allosteric inhibition of the IRE1? RNase preserves cell viability and function during endoplasmic reticulum stress.

ABSTRACT: Depending on endoplasmic reticulum (ER) stress levels, the ER transmembrane multidomain protein IRE1? promotes either adaptation or apoptosis. Unfolded ER proteins cause IRE1? 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, IRE1? 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 IRE1? Kinase-Inhibiting RNase Attenuators-KIRAs-that allosterically inhibit IRE1?'s RNase by breaking oligomers. One optimized KIRA, KIRA6, inhibits IRE1? 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 ? cells, increases insulin, and reduces hyperglycemia in Akita diabetic mice. Thus, IRE1? powerfully controls cell fate but can itself be controlled with small molecules to reduce cell degeneration.

SUBMITTER: Ghosh R 

PROVIDER: S-EPMC4244221 | biostudies-literature | 2014 Jul

REPOSITORIES: biostudies-literature