IRE1 drives a homeostatic response to reduced protein influx into the endoplasmic reticulum (ISR Timecourse)

Two modes of IRE1 activation are known: i) in response to an accumulation of unfolded proteins in the ER lumen and ii) in response to compositional changes to the ER membrane that alter its physical properties. Here, we identify a third, independent mode of IRE1 activation: ER co-translational translocation deficits activate IRE1 through a mechanism that relies on the release of IRE1 molecules from unoccupied translocons.

We define this mechanism as TRES for “TRanslocon Engagement Surveillance”. TRES leads to spontaneous activation of IRE1 and bypasses its unfolded protein- and ER membrane composition-sensing functions. Inhibiting translation initiation similarly activates IRE1 by TRES, as it leads to a decline in ER protein import, thus linking the integrated stress response (ISR) to IRE1 signaling.