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Journal article
Inhibitors of eIF4G1-eIF1 uncover its regulatory role of ER/UPR stress-response genes independent of eIF2α-phosphorylation
Proceedings of the National Academy of Sciences - PNAS, Vol.119(30), e2120339119
20/Jul/2022
Abstract
During translation initiation, eIF4G1 dynamically interacts with eIF4E and eIF1. While the role of eIF4E–eIF4G1 is well established, the regulatory functions of eIF4G1–eIF1 are poorly understood. Here, we report the identification of the eIF4G1–eIF1 inhibitors i14G1-10 and i14G1-12. i14G1s directly bind eIF4G1 and inhibit translation in vitro and in the cell, and their effects on translation are dependent on eIF4G1 levels. Translatome analyses revealed that i14G1s mimic eIF1 and eIF4G1 perturbations on the stringency of start codon selection and the opposing roles of eIF1–eIF4G1 in scanning-dependent and scanning-independent short 5′ untranslated region (UTR) translation. Remarkably, i14G1s activate ER/unfolded protein response (UPR) stress-response genes via enhanced ribosome loading, elevated 5′UTR translation at near-cognate AUGs, and unexpected concomitant up-regulation of coding-region translation. These effects are, at least in part, independent of eIF2α-phosphorylation. Interestingly, eIF4G1–eIF1 interaction itself is negatively regulated by ER stress and mTOR inhibition. Thus, i14G1s uncover an unknown mechanism of ER/UPR translational stress response and are valuable research tools and potential drugs against diseases exhibiting dysregulated translation.
Details
- Title
- Inhibitors of eIF4G1-eIF1 uncover its regulatory role of ER/UPR stress-response genes independent of eIF2α-phosphorylation
- Creators
- Urmila Sehrawat - 972WIS_INST___112Ora Haimov - 972WIS_INST___112Benjamin Weiss - 972WIS_INST___112Ana Tamarkin-Ben Harush - 972WIS_INST___112Shaked Ashkenazi - 972WIS_INST___112Alexander Plotnikov - 972WIS_INST___890Tzahi Noiman - 972WIS_INST___111Dena Leshkowitz - 972WIS_INST___113Gil Stelzer - 972WIS_INST___113Rivka Dikstein (Corresponding Author) - 972WIS_INST___112
- Resource Type
- Journal article
- Publication Details
- Proceedings of the National Academy of Sciences - PNAS, Vol.119(30), e2120339119; 20/Jul/2022
- Language
- English
- DOI
- https://doi.org/10.1073/pnas.2120339119
- Grant note
- We thank Dr. Haim Barr and Galit Cohen from the Wohl Drug Discovery Institute of the Nancy and Stephen of G-INCPM (Weizmann Institute of Science) for their drug screening services; Prof. Chaim Kahana (Weizmann Institute, Israel) for providing us the S52A eIF2α mutant cells; Dr. Anat Bahat from our laboratory for her contribution to the drug screen and for reading and commenting on the manuscript; Dr. Sima Benjamin formerly from the Crown Genomics Institute of the Nancy and Stephen G-INCPM for the RNA-seq services, and Dr. Ariel Ogran for his bioinformatics assistance, and Dr. Alexander Brandis from the Targeted Metabolomics Unit (Weizmann Institute of Science, Core facilities) for the liquid chromatography–mass spectrometry analysis. This work was supported by grants from the Israel Science Foundation (No. 843/17) and the Minerva Foundation (No. 713877) and by internal grants from Dr. Barry Sherman Institute for Medicinal Chemistry; Estate of Albert Engleman; Estate of David Levinson; and a fellowship from the Society of Swiss Friends of the Weizmann Institute of Science (to B.W.). R.D. is the incumbent of the Ruth and Leonard Simon Chair of Cancer Research.
- Record Identifier
- 993401083203596
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