Dynamic changes in oligomeric complexes of UPR sensors induced by misfolded proteins in the ER

The endoplasmic reticulum (ER) localized unfolded protein response (UPR) sensors, IRE1α, PERK, and ATF6α, are activated upon accumulation of misfolded proteins caused by ER stress. It is debated whether these UPR sensors are activated either by the release of their negative regulator BiP chaperone or directly binding to misfolded proteins during ER stress. Here we simultaneously examined oligomerization and activation of all three endogenous UPR sensors. We found that UPR sensors existed as preformed oligomers even in unstressed cells, which shifted to large oligomers for PERK and small oligomers for ATF6α, but little changed for IRE1α upon ER stress. Neither depletion nor overexpression of BiP had significant effects on oligomeric complexes of UPR sensors both in unstressed and stressed cells. Thus, our results find less evidence for the BiP-mediated activation of UPR sensors in mammalian cells and support that misfolded proteins bind and activate the preformed oligomers of UPR sensors.