Ribosome collisions trigger cis-acting feedback inhibition of translation initiation
- MRC Laboratory of Molecular Biology, United Kingdom
- MRC-Laboratory of Molecular Biology, United Kingdom
Abstract
Translation of aberrant mRNAs can cause ribosomes to stall, leading to collisions with trailing ribosomes. Collided ribosomes are specifically recognized by ZNF598 to initiate protein and mRNA quality control pathways. Here we found using quantitative proteomics of collided ribosomes that EDF1 is a ZNF598-independent sensor of ribosome collisions. EDF1 stabilizes GIGYF2 at collisions to inhibit translation initiation in cis via 4EHP. The GIGYF2 axis acts independently of the ZNF598 axis, but each pathway's output is more pronounced without the other. We propose that the widely conserved and highly abundant EDF1 monitors the transcriptome for excessive ribosome density, then triggers a GIGYF2-mediated response to locally and temporarily reduce ribosome loading. Only when collisions persist is translation abandoned to initiate ZNF598-dependent quality control. This tiered response to ribosome collisions would allow cells to dynamically tune translation rates while ensuring fidelity of the resulting protein products.
Data availability
All data generated or analyzed during this study are included in the manuscript and supporting files. Source data have been provided for Figure 1.
Article and author information
Author details
Szymon Juszkiewicz
Funding
Medical Research Council (MC_UP_A022_1007)
- Ramanujan S Hegde
The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.
Copyright
© 2020, Juszkiewicz et al.
This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.
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Ribosome collisions trigger cis-acting feedback inhibition of translation initiation
eLife 9:e60038.
https://doi.org/10.7554/eLife.60038
