Targeted Protein Destabilization Reveals an Estrogen-mediated ER Stress Response

Accumulation of unfolded proteins within the endoplasmic reticulum (ER) of eukaryotic cells leads to an unfolded protein response (UPR) that either restores homeostasis or commits the cells to apoptosis. Tools traditionally used to study the UPR are pro-apoptotic and thus confound analysis of long-term cellular responses to ER stress. Here, we describe an Endoplasmic Reticulum-localized HaloTag (ERHT) protein that can be conditionally destabilized using a small molecule hydrophobic tag (HyT36). Treatment of ERHT-expressing cells with HyT36 induces an acute, resolvable ER stress that results in transient UPR activation without induction of apoptosis. Transcriptome analysis of late-stage responses to this UPR stimulus reveals a link between UPR activity and estrogen signaling.