Cell doi:10.1016/j.cell.2014.07.002

Credit: ELSEVIER

Unfolded proteins in the endoplasmic reticulum (ER) trigger an unfolded protein response (UPR) to ensure the restoration of protein homeostasis. One of the signaling outputs for the UPR, IRE1α, senses unfolded proteins through its lumenal domain, triggering IRE1α oligomerization and trans-autophosphorylation of the kinase domain, thus activating the adjacent RNase domain, which cleaves the XBP1 transcription factor. This process, which results in an adaptive UPR, differs from a terminal UPR, which occurs under high or unresolvable protein stress. In a terminal UPR, IRE1α cleaves a larger number of ER mRNA targets (called extra-XBP1 cleavage) in pancreatic islets or photoreceptors, eventually resulting in apoptosis in these cell types. As oligomerization precedes trans-autophosphorylation and mRNA cleavage, Ghosh et al. predicted that a particular threshold in IRE1α oligomerization levels could bias this switch between survival and death. IRE1α variants known to undergo robust activation and oligomerization underwent extra-XBP1 RNA cleavage and apoptosis, whereas cancer mutations that intermediately activate UPR signaling fail to undergo apoptosis. Application of a potent type II IRE1α kinase inhibitor (KIRA6), which allosterically blocked RNase activity and oligomerization, prevented extra-XBP1 cleavage and apoptosis in ER-stressed cells. Finally, treatment with KIRA6 in animal models of photoreceptor or islet degeneration due to terminal UPR signaling was able to significantly preserve the functioning mass of cells. These findings suggest that the level of IRE1α oligomerization can trigger distinct physiological outputs that dictate cell survival or death.