In eukaryotic cells, the accumulation of unfolded proteins in the endoplasmic reticulum (ER) triggers a signaling pathway from the ER to the nucleus. Several yeast mutants defective in this pathway map to the ERNl gene, which protects cells from lethal consequences of stress by signaling for increased expression of BiP and other ER proteins. ERN7 encodes a 1115 amino acid transmembrane protein (Ernlp) whose glycosylated N-terminal portion is located inside microsomes and whose cytoplasmic C-terminal portion carries an essential protein kinase activity. We postulate that Ernlp is the proximal sensor of events in the ER and that binding of ligand causes transduction of information across the ER membrane, leading to activation of a specific set of transcription factors. introduction

Secretory and transmembrane proteins flux through the endoplasmic reticulum (ER) on their way to the cell surface. Translocated in an unfolded state, the newly synthesized polypeptides are prepared for onward transport by a variety of proteins resident in the ER that help exocytotic proteins fold into their correct tertiary and quaternary structures (reviewed by Gething and Sambrook, 1992). Passenger proteins resume their migration to the cell surface only after folding is essentially complete. The ER is therefore a specialized organelle that not only provides conditions favorable for the import and folding of exocytotic proteins but also discriminates between folded and unfolded protein structures. BiP, a member of the stress 70 (hsp70) family of chaperone proteins, plays an essential role in these processes. In Saccharomyces cerevisiae, BiP is required both for translocation of nascent proteins across the ER membrane (Vogel et al., 1990; Nguyen et al., 1991; Sanders et al., 1992) and for their subsequent folding and assembly (Schonberger et al., 1991). In mammalian cells, BiP, which constitutes 5%-l 0% of the luminal protein of the ER, associates transiently with a wide variety of newly synthesized wild-type secretory and integral membrane proteins and more permanently with polypeptides that are are unable to fold into a native configuration (reviewed by Gething and Sambrook, 1992). BiP mRNA is synthesized constitutively in both mammalian cells and yeasts, and transcription of the BiP gene is further induced by the presence of mutant or malfolded pro-