Work

EDF1 coordinates cellular responses to ribosome collisions

Year: 2020

Type: article

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.

Source: eLife

DOI: 10.7554/elife.58828

Authors: Niladri K Sinha, Alban Ordureau, Katharina Best, James A Saba, Boris Zinshteyn, Elayanambi Sundaramoorthy, Amit Fulzele, Danielle M Garshott, Timo Denk, Matthias Thoms, Joao A Paulo, J Wade Harper, Eric J Bennett, Roland Beckmann, Rachel Green

Institutions: Howard Hughes Medical Institute, Johns Hopkins University, Harvard University, Ludwig-Maximilians-Universität München, University of California San Diego

Language: English

Topic: RNA and protein synthesis mechanisms

Subfield: Molecular Biology

Field: Biochemistry, Genetics and Molecular Biology

Domain: Life Sciences

Open Access status: gold

Estimated APC paid: $2,500

Funders: National Science Foundation, Howard Hughes Medical Institute, Jane Coffin Childs Memorial Fund for Medical Research, Deutsche Forschungsgemeinschaft, National Institutes of Health, National Institute on Aging, National Institute of General Medical Sciences, National Institute of Neurological Disorders and Stroke

Awards: G1030352103, Graduate Research Fellowship Program (GRFP), G149138245, G1689724940, Molecular mechanisms of ribosome pausing and the cellular response, Cell and Molecular Genetics Training Program, G2347260615, G2853362361, Mechanisms for establishment and recognition of stop codon context, G4104527358, G467560643, Systematic discovery and functional analysis of the PARKIN modified proteome, G6587270076, Defining the function and mechanism of regulatory ribosomal ubiquitylation, G8740624389, G9000018185, Medical Scientist Training Program, G917839695

OpenAlex ID: W3046992336

FWCI: 5.805

Cites: 103

Cited by: 179

Related to: 10