A Novel Mechanism for Regulating Activity of a Transcription Factor That Controls the Unfolded Protein Response

AbstractCells respond to an accumulation of unfolded proteins in the endoplasmic reticulum (ER) by increasing transcription of genes encoding ER–resident proteins. The information is transmitted from the ER lumen to the nucleus by an intracellular signaling pathway, the unfolded protein response (UPR). We have identified a basic–leucine zipper transcription factor, Hac1p, that is required for the UPR and binds to the UPR element in the promoter of UPR–regulated genes. Surprisingly, Hac1p is found in UPR–activated cells only, and its level is controlled by regulated splicing of its mRNA. Splicing replaces the C-terminal tail of Hac1p with a different peptide that renders Hac1p more resistant to an otherwise extremely rapid ubiquitin-dependent degradation. We propose that the complex regulation of Hac1p expression serves to provide multiple levels at which the UPR can be controlled