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

Authors
  • Oltion, Keely1
  • Carelli, Jordan D1
  • Yang, Tangpo2
  • See, Stephanie K1
  • Wang, Hao-Yuan2
  • Kampmann, Martin3
  • Taunton, Jack4
  • 1 Chemistry and Chemical Biology Graduate Program, University of California, San Francisco, San Francisco, CA 94158, USA.
  • 2 Department of Cellular and Molecular Pharmacology, University of California, San Francisco, San Francisco, CA 94158, USA.
  • 3 Institute for Neurodegenerative Diseases, Department of Biochemistry and Biophysics, University of California, San Francisco, San Francisco, CA 94158, USA; Chan Zuckerberg Biohub, San Francisco, CA 94158, USA.
  • 4 Department of Cellular and Molecular Pharmacology, University of California, San Francisco, San Francisco, CA 94158, USA. Electronic address: [email protected].
Type
Published Article
Journal
Cell
Publication Date
Jan 19, 2023
Volume
186
Issue
2
Identifiers
DOI: 10.1016/j.cell.2022.12.025
PMID: 36638793
Source
Medline
Keywords
Language
English
License
Unknown

Abstract

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. Copyright © 2022 Elsevier Inc. All rights reserved.

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