New Insights into Translational Regulation in the Endoplasmic Reticulum Unfolded Protein Response

Homeostasis of the protein-folding environment in the endoplasmic reticulum (ER) is main-tained by signal transduction pathways that collectively constitute an unfolded protein re-sponse (UPR). These affect bulk protein synthesis and thereby the levels of ER stress, but also culminate in regulated expression of specificmRNAs, such as that encoding the transcription factor ATF4. Mechanisms linking eukaryotic initiation factor 2 (eIF2) phosphorylation to control of unfolded protein load in the ER were elucidated more than 10 years ago, but recent work has highlighted the diversity of processes that impinge on eIF2 activity and revealed that there aremultiplemechanisms bywhich changes in eIF2 activity canmodulate the translation of individual mRNAs. In addition, the potential for affecting this step of translation initiation pharmacologically is becoming clearer. Furthermore, it is now clear that another strand of the UPR, controlled by the endoribonuclease inositol-requiring enzyme 1 (IRE1), also affects rates of protein synthesis in stressed cells and that its effector function, mediated by the transcription factor X-box-binding protein 1 (XBP1), is subject to important mRNA-specific translational regulation. These new insights into the convergence of translational control and the UPR will be reviewed here