Dynamic interaction of BiP and ER stress transducers in the unfolded-protein response

PERK and IRE1 are type-I transmembrane protein kinases that reside in the e ndoplasmic reticulum (ER) and transmit stress signals in response to pertur bation of protein folding. Here we show that the lumenal domains of these t wo proteins are functionally interchangeable in mediating an ER stress resp onse and that, in unstressed cells, both lumenal domains form a stable comp lex with the ER chaperone BiP. Perturbation of protein folding promotes rev ersible dissociation of BiP from the lumenal domains of PERK and IRE1. Loss of BiP correlates with the formation of high-molecular-mass complexes of a ctivated PERK or IRE1, and overexpression of BiP attenuates their activatio n. These findings are consistent with a model in which BiP represses signal ling through PERK and IRE1 and protein misfolding relieves this repression by effecting the release of BiP from the PERK and IRE1 lumenal domains.