BiP Binding to the ER-Stress Sensor Ire1 Tunes the Homeostatic Behavior of the Unfolded Protein Response

TLDR

The unfolded protein response (UPR) is an intracellular signaling pathway that counteracts stresses impairing protein folding in the endoplasmic reticulum and acts as a homeostat tuning ER folding capacity to demand. This study aims to clarify how the ER stress sensor Ire1 is activated by unfolded proteins and the role of the chaperone BiP in regulating Ire1 activity. BiP regulates Ire1 by sequestering inactive molecules, preventing their oligomerization and facilitating de‑oligomerization, thereby controlling Ire1 activation and deactivation. The authors demonstrate that UPR output scales with stress magnitude by modulating Ire1 signaling duration, with BiP desensitizing Ire1 to low stress and buffering inactive Ire1 to fine‑tune sensitivity and restore protein folding homeostasis.

Abstract

The unfolded protein response (UPR) is an intracellular signaling pathway that counteracts variable stresses that impair protein folding in the endoplasmic reticulum (ER). As such, the UPR is thought to be a homeostat that finely tunes ER protein folding capacity and ER abundance according to need. The mechanism by which the ER stress sensor Ire1 is activated by unfolded proteins and the role that the ER chaperone protein BiP plays in Ire1 regulation have remained unclear. Here we show that the UPR matches its output to the magnitude of the stress by regulating the duration of Ire1 signaling. BiP binding to Ire1 serves to desensitize Ire1 to low levels of stress and promotes its deactivation when favorable folding conditions are restored to the ER. We propose that, mechanistically, BiP achieves these functions by sequestering inactive Ire1 molecules, thereby providing a barrier to oligomerization and activation, and a stabilizing interaction that facilitates de-oligomerization and deactivation. Thus BiP binding to or release from Ire1 is not instrumental for switching the UPR on and off as previously posed. By contrast, BiP provides a buffer for inactive Ire1 molecules that ensures an appropriate response to restore protein folding homeostasis to the ER by modulating the sensitivity and dynamics of Ire1 activity.