Cell 158, 1362–1374 (2014)

The unfolded protein response (UPR) pathway helps cells counteract stress that perturbs folding of proteins in the endoplasmic reticulum (ER). UPR resets proteostasis by lowering protein flux into the ER through translational downregulation or mRNA turnover and by elevating the expression of ER proteins that manage accumulated unfolded proteins. Reid et al. now report a new pathway that limits protein transit into the ER by dynamic relocalization of mRNA and ribosomes to the cytoplasm. Using thapsigargin and dithiothreitol as reagents to induce protein folding stress in cells, the authors assessed the location and activity of translation over time using ribosome profiling and RNA-seq. Their analysis suggests that early UPR focuses on lowering translational efficiency—particularly for the subset of ER-tethered polyribosomes that are translating mRNAs for membrane and secretory proteins—in a rapid process that involves selective release of these mRNA–ribosome complexes into the cytoplasm, where they may continue translation. This pathway is also reversible, as kinetic analysis revealed that this translating pool of mRNAs becomes relocalized to the ER membrane upon removal of folding stress. Though additional studies will be needed to identify the molecular interactions that regulate ribosome tethering and release at the ER, the current model provides a new mechanism for reducing protein flux stress at the ER during the early stages of UPR.