The Oligomerization Status of IRE1α Kinase/RNase Determines Its Signaling Outputs Under Endoplasmic Reticulum Stress

Accumulation of unfolded proteins in the endoplasmic reticulum (ER) triggers signaling pathways called the unfolded protein response (UPR). Under remediable levels of ER stress, the adaptive UPR (A‐UPR) activates transcriptional and translational changes that restore homeostasis. However, under irremediably high ER stress, these adaptive measures fail and the signaling pathways instead trigger programmed cell death—referred to as the terminal UPR (T‐UPR). We discovered that IRE1α—an ER transmembrane bifunctional kinase/endoribonuclease (RNase)—is a critical life‐death switch that employs kinase auto‐phosphorylation levels as a mechanism to control its filamentous status and toggle between an A‐UPR or a T‐UPR depending on the level of upstream ER stress. Remediable ER stress causes low‐level kinase auto‐phosphorylation and dimerization that restricts IRE1α’s RNase activity to excising an intron in XBP1 mRNA, which upon re‐ligation and translation of spliced XBP1 produces the homeostatic transcription factor XBP1s (s=spliced) that then upregulates genes encoding ER protein‐folding and quality control components. However, s ustained ER stress induces high‐level kinase autophosphorylation to promote higher‐order IRE1α oligomerization; under these conditions, IRE1α RNase hyperactivation leads to massive degradation of ER‐localized mRNA and T‐UPR events including: (1) loss of differentiated cell identity, (2) local sterile inflammation, and (3) programmed cell death through pyroptosis and apoptosis. We have recent insights into how the oligomerization status and signaling outputs of IRE1α contribute to cancer. Support or Funding Information The work was supported by grants: American Cancer Society Research Scholar Award; Harrington Discovery Institute Scholar‐Innovator Award; UCSF and Onyx Oncology Innovation Alliance; American Association of Cancer Research; R01CA219815; R01EY027810.