An E3 ligase network engages GCN1 to promote the degradation of translation factors on stalled ribosomes.

Ribosomes frequently stall during mRNA translation, resulting in the context-dependent activation of quality control pathways to maintain proteostasis. However, surveillance mechanisms that specifically respond to stalled ribosomes with an occluded A site have not been identified. We discovered that the elongation factor-1? (eEF1A) inhibitor, ternatin-4, triggers the ubiquitination and degradation ...
of eEF1A on stalled ribosomes. Using a chemical genetic approach, we unveiled a signaling network comprising two E3 ligases, RNF14 and RNF25, which are required for eEF1A degradation. Quantitative proteomics revealed the RNF14 and RNF25-dependent ubiquitination of eEF1A and a discrete set of ribosomal proteins. The ribosome collision sensor GCN1 plays an essential role by engaging RNF14, which directly ubiquitinates eEF1A. The site-specific, RNF25-dependent ubiquitination of the ribosomal protein RPS27A/eS31 provides a second essential signaling input. Our findings illuminate a ubiquitin signaling network that monitors the ribosomal A site and promotes the degradation of stalled translation factors, including eEF1A and the termination factor eRF1.
Mesh Terms:
Carrier Proteins, HEK293 Cells, HeLa Cells, Humans, Peptide Elongation Factor 1, Peptide Elongation Factors, Protein Biosynthesis, RNA-Binding Proteins, Ribosomal Proteins, Ribosomes, Trans-Activators, Ubiquitin-Protein Ligases, Ubiquitination
Cell
Date: Jan. 19, 2023
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