Amino Acid Biosynthesis Regulation during Endoplasmic Reticulum Stress Is Coupled to Protein Expression Demands

The endoplasmic reticulum (ER) stress response, also known as the unfolded protein response (UPR), is a complex cellular response to ER protein misfolding that involves transcriptional regulatory branches and a PERK-mediated translational regulatory branch. Here we revealed that amino acid biosynthesis regulation is coupled to protein synthesis demands during ER stress. Specifically, we demonstrated that the UPR leads to PERK-dependent induction in the biosynthesis of specific amino acids, and to upregulation of their corresponding tRNA synthetases. Furthermore, we found that sequences of UPR-upregulated proteins are significantly enriched with these UPR-induced amino acids. Interestingly, whereas the UPR leads to repression of ER target proteins, we showed that secreted proteins tended to escape this repression and were highly enriched for the UPR-induced amino acids. Our results unravel coordination between amino acid supply, namely, biosynthesis and tRNA loading, and demand from UPR-induced proteins under ER stress, thus revealing an additional regulatory layer of protein synthesis.