Translational profiling in the unfolded protein response

The unfolded protein response (UPR) couples cellular translation rates and gene expression to the protein folding status of the endoplasmic reticulum (ER). Upon activation, the UPR machinery elicits a general suppression of protein synthesis and activation of stress gene expression, which act coordinately to restore protein folding homeostasis. We report here that UPR activation promotes the release of signal sequence-encoding mRNAs from the ER to the cytosol as a mechanism to decrease protein influx into the ER. This release of mRNA begins rapidly, then gradually recovers with ongoing stress. Upon release into the cytosol, these mRNAs have divergent fates: some synthesize full-length proteins, while others are translationally inactive and retain nascent protein chains. Together, these findings identify the dynamic subcellular localization of mRNAs and translation as a regulatory feature of the cellular response to protein folding stress. Cells were treated with a timecourse of Thapsigargin or DTT, then fractionated and analyzed by mRNA-seq or ribosome profiling