When demands on the protein folding machinery get too great, how does the cell know? Using a series of yeast mutants, Kimata et al. now suggest that oligomerization allows an ER stress sensor protein to recognize unfolded protein and signal distress.
Yeast's sole ER stress sensor is Ire1. It sits in the ER membrane and binds a chaperone called BiP on its luminal domain. Upon ER stress—the accumulation of unfolded proteins in the ER—BiP dissociates, and Ire1 autophosphorylates. This starts a signaling cascade that promotes production of a transcription factor that activates ER stress relief genes.
BiP dissociation is not sufficient for activating Ire1, however; removal of the BiP-binding domain does not lead to constitutive activation, although Ire1 can still respond to ER stress. As the authors now show, BiP dissociation serves only to allow Ire1 monomers to oligomerize.
In turn, oligomerization allowed Ire1 to form a domain that recognized unfolded proteins, a step that is necessary for Ire1 activation. In vitro experiments confirmed that this domain of Ire1 directly binds unfolded proteins, although it is not yet clear how binding enables Ire1 activation. Given that certain conformational mutants of Ire1 are constitutively active, the authors suggest that the unfolded proteins probably trigger conformational changes that enable autophosphorylation and action. Why BiP is needed in this equation is yet to be determined.