An E3 ligase network engages GCN1 to promote the degradation of translation factors on stalled ribosomes.
An E3 ligase network engages GCN1 to promote the degradation of translation factors on stalled ribosomes.
复制标题
E3 连接酶网络与 GCN1 结合，促进停滞核糖体上翻译因子的降解。
DOI：
10.1016/j.cell.2022.12.025
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发表时间：
2023
期刊：
影响因子：
64.5
通讯作者：
Taunton,Jack
中科院分区：
文献类型：
--
作者：
Oltion,Keely;Carelli,JordanD;Yang,Tangpo;See,StephanieK;Wang,Hao-Yuan;Kampmann,Martin;Taunton,Jack
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-1α (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.
