Dissociation of Kar2p/BiP from an ER sensory molecule, Ire1p, triggers theunfolded protein response in yeast

The unfolded protein response (UPR) is a signal transduction pathway induce d by a variety of endoplasmic reticulum (ER) stresses and functions to main tain homeostasis of the cellular membrane in eukaryotes. Various ER stresse s result in the accumulation of unfolded proteins in the ER, which is sense d by the transmembrane protein kinase/ribonuclease Ire1p that transmits a s ignal from the ER to the nucleus in Saccharomyces cerevisiae. Here we repor t that the yeast ER chaperone Kar2p/BiP, a member of the HSP70 family found in the ER, directly regulates the UPR by the interaction with Ire1p. In th e absence of ER stress, Kar2p binds the lumenal domain of Ire1p and keeps I re1p in an inactive unphosphorylated state. Upon exposure of cells to ER st resses, Kar2p is released from Ire1p, resulting in activation of Ire1p and signal transduction to the nucleus. Subsequently, KAR2 mRNA is induced and Kar2p accumulates in the ER in a time-dependent manner, restoring the syste m to the basal state. This negative autoregulation is similar to the regula tion of mammalian cytosolic chaperone Hsp70 via its interaction with heat s hock factor 1. (C) 2000 Academic Press.