@article{2db7968864b040d8a72f919bcc7280a1,
title = "EDF1 coordinates cellular responses to ribosome collisions",
abstract = "Translation of aberrant mRNAs induces ribosomal collisions, thereby triggering pathways for mRNA and nascent peptide degradation and ribosomal rescue. Here we use sucrose gradient fractionation combined with quantitative proteomics to systematically identify proteins associated with collided ribosomes. This approach identified Endothelial differentiation-related factor 1 (EDF1) as a novel protein recruited to collided ribosomes during translational distress. Cryo-electron microscopic analyses of EDF1 and its yeast homolog Mbf1 revealed a conserved 40S ribosomal subunit binding site at the mRNA entry channel near the collision interface. EDF1 recruits the translational repressors GIGYF2 and EIF4E2 to collided ribosomes to initiate a negative-feedback loop that prevents new ribosomes from translating defective mRNAs. Further, EDF1 regulates an immediate-early transcriptional response to ribosomal collisions. Our results uncover mechanisms through which EDF1 coordinates multiple responses of the ribosome-mediated quality control pathway and provide novel insights into the intersection of ribosome-mediated quality control with global transcriptional regulation.",
author = "Sinha, {Niladri K.} and Alban Ordureau and Best, {Katharina M.} and Saba, {James A.} and Boris Zinshteyn and Elayanambi Sundaramoorthy and Amit Fulzele and Garshott, {Danielle M.} and Timo Denk and Matthias Thoms and Paulo, {Joao A.} and Harper, {J. Wade} and Bennett, {Eric J.} and Roland Beckmann and Rachel Green",
note = "Funding Information: We would like to thank Colin Wu for thoughtful discussions and critical reading of this manuscript; members of the Green lab, especially Jamie Wangen, for advice and helpful feedback throughout; Dr. Aitor Garzia and Dr. Thomas Tuschl for their kind gift of the HEK293 Flp-In T-Rex ∆ZNF598 cell line (Garzia et al., 2017); Dr. Andrew Holland and Gina Lomastro for sharing the pLentiCRISPRv2 plasmid and assistance generating the ∆EDF1 and ∆EDF1∆ZNF598 cell lines; Dr. Shintaro Iwasaki for sharing the psiCHECK2-Renilla-2A-3xFLAG-MsXbp1u-2A-Firefly plasmid; Dr. Elizabeth J. Grayhack for initial reagents for Mbf1; Dr. Otto Berninghausen for cryo-EM data collection; Lauren DeVine and Dr. Robert N. Cole at the JHMI Mass Spectrometry and Proteomics Facility for mass-spec support. Funding: This work was supported by the Howard Hughes Medical Institute to R.G., National Institutes of Health grants R37GM059425 to R.G., Deutsche Forschungsgemeinschaft GRK 1721 to R.B., AG011085 and R37NS083524 to J.W.H., RO1GM132129 to J.A.P., DP2GM119132 to E.J.B., 5K99GM135450-02 to B.Z., and UL1TR003098 to the JHMI Mass Spectrometry and Proteomics Facility. N.K.S is an HHMI fellow of the Jane Coffin Childs Memorial Fund for Medical Research. K.M.B and T.D. are supported by Deutsche Forschungsgemeinschaft (QBM (Quantitative Biosciences Munich) Graduate School Fellowships). D.M.G. is supported by a UCSD Cell and Molecular Genetics Training Program (T32GM007240) and a National Science Foundation Graduate Research Fellowship (DGE-1650112). Publisher Copyright: {\textcopyright} 2020, eLife Sciences Publications Ltd. All rights reserved.",
year = "2020",
month = aug,
doi = "10.7554/ELIFE.58828",
language = "English (US)",
volume = "9",
pages = "1--84",
journal = "eLife",
issn = "2050-084X",
publisher = "eLife Sciences Publications",
}