Figure 7.

IRE1 Repression by ERdj4 and BiP and Activation by Unfolded Proteins

In the unstressed ER (green shading), ERdj4 binds the IRE1 CLD via its C-terminal targeting domain. ERdj4 stimulates BiP’s ATPase activity to promote BiP binding to IRE1, ejection of ERdj4, and formation of a repressive BiP-IRE1 complex with a disrupted dimer interface. The BiP-IRE1 complex turns over by nucleotide exchange. Free ERdj4 and BiP recruit the released IRE1 (either as a monomer or dimer) in a kinetically maintained repressive cycle. Accumulating unfolded proteins during ER stress (red shading) compete for BiP and/or ERdj4, interrupting the cycle of repression. IRE1 monomers are free to dimerize and activate downstream signals.