biostudies-literatureGardner BMNCRR NIH HHSNIGMS NIH HHSa013169https://www.ebi.ac.uk/biostudies/studies/S-EPMC3578356biostudies-literatureUnknown5(3)Secretory and transmembrane proteins enter the endoplasmic reticulum (ER) as unfolded proteins and exit as either folded proteins in transit to their target organelles or as misfolded proteins targeted for degradation. The unfolded protein response (UPR) maintains the protein-folding homeostasis within the ER, ensuring that the protein-folding capacity of the ER meets the load of client proteins. Activation of the UPR depends on three ER stress sensor proteins, Ire1, PERK, and ATF6. Although the consequences of activation are well understood, how these sensors detect ER stress remains unclear. Recent evidence suggests that yeast Ire1 directly binds to unfolded proteins, which induces its oligomerization and activation. BiP dissociation from Ire1 regulates this oligomeric equilibrium, ultimately modulating Ire1's sensitivity and duration of activation. The mechanistic principles of ER stress sensing are the focus of this review.Cold Spring Harbor perspectives in biologyEndoplasmic reticulum stress sensing in the unfolded protein response.PMC35783562P41RR001081P41 GM103311P41 RR0010819P41GM103311Gallagher CMGardner BMGotthardt KPincus DWalter PfalseEndoplasmic reticulum stress sensing in the unfolded protein response.Secretory and transmembrane proteins enter the endoplasmic reticulum (ER) as unfolded proteins and exit as either folded proteins in transit to their target organelles or as misfolded proteins targeted for degradation. The unfolded protein response (UPR) maintains the protein-folding homeostasis within the ER, ensuring that the protein-folding capacity of the ER meets the load of client proteins. Activation of the UPR depends on three ER stress sensor proteins, Ire1, PERK, and ATF6. Although the consequences of activation are well understood, how these sensors detect ER stress remains unclear. Recent evidence suggests that yeast Ire1 directly binds to unfolded proteins, which induces its oligomerization and activation. BiP dissociation from Ire1 regulates this oligomeric equilibrium, ultimately modulating Ire1's sensitivity and duration of activation. The mechanistic principles of ER stress sensing are the focus of this review.2013-01-01T00:00:00Z2013 Mar2020-11-19T14:28:56Z2019-03-27T01:05:03ZS-EPMC35783562338862610.1101/cshperspect.a013169