Pii: S0962-8924(98)01267-7

Copyright © 1998 Elsevier Science Ltd. All rights reserved. 0962-8924/98/$19.00 245 PII: S0962-8924(98)01267-7 The unfolded protein response (UPR) is induced following the accumulation of unfolded proteins in the lumen of the endoplasmic reticulum (ER) and results in the upregulation of genes encoding ER-resident enzymes involved in protein folding1–3. Thus, the cell is able to increase the folding capacity of the ER according to need. The target genes of the UPR share a common upstream activating sequence in their promoters, the unfolded protein response element (UPRE), that directs their transcription upon induction of the pathway4. The existence of this common element suggested early on that the pathway is controlled by a common transcription factor whose activity is regulated by the conditions in the ER lumen. Although the UPR exists in all eukaryotic cells, much of the progress in understanding this signalling pathway comes from recent studies in the yeast Saccharomyces cerevisiae. Starting with genetic approaches to dissect the molecular mechanism of the UPR pathway, IRE15,6 was identified as the first gene known to be required for a functional UPR. IRE1 encodes a transmembrane protein similar in structure to mammalian growth-factor receptor kinases. Ire1p resides in the ER or inner nuclear membrane (with which the ER is continuous), with its N-terminal half facing the ER lumen, and its C-terminal half – which contains the kinase domain – facing the nucleus or cytoplasm. In this orientation, the N-terminal half is thought to serve as a sensor domain that detects the accumulation of unfolded proteins in the ER lumen, whereas its kinase domain would function in the cytoplasm or nucleus to activate downstream events in the pathway. Thus, the structure and topology of Ire1p make it ideally suited to function as the proximal sensor of the conditions in the ER lumen and to be the signal-transduction device that transmits this information across the membrane. Upon induction of the UPR, Ire1p oligomerizes in the plane of the membrane and becomes transautophosphorylated by neighbouring Ire1p molecules7. How does Ire1p activation lead to induction of downstream events in the signalling pathway? By analogy to signal-transduction pathways that operate downstream of other serine/threonine kinase receptors, the expectation was that Ire1p would activate a kinase cascade leading to phosphorylation and activation of a downstream transcription factor. Recent work, however, has revealed a remarkably different signaltransduction pathway downstream of Ire1p. Here, we describe the series of unexpected results that allowed the elucidation of the unique signalling events that control the UPR.