2. Academic Validation
  3. Drug-induced eRF1 degradation promotes readthrough and reveals a new branch of ribosome quality control

Drug-induced eRF1 degradation promotes readthrough and reveals a new branch of ribosome quality control

  • Cell Rep. 2023 Sep 26;42(9):113056. doi: 10.1016/j.celrep.2023.113056.
Lukas-Adrian Gurzeler 1,  Marion Link 2,  Yvonne Ibig 2,  Isabel Schmidt 2,  Olaf Galuba 2,  Julian Schoenbett 2,  Christelle Gasser-Didierlaurant 2,  Christian N Parker 2,  Xiaohong Mao 3,  Francis Bitsch 2,  Markus Schirle 3,  Philipp Couttet 2,  Frederic Sigoillot 3,  Jana Ziegelmüller 1,  Anne-Christine Uldry 4,  Wojciech Teodorowicz 1,  Niko Schmiedeberg 2,  Oliver Mühlemann 5,  Jürgen Reinhardt 6
Affiliations

Affiliations

  • 1 Department of Chemistry, Biochemistry and Pharmaceutical Sciences, University of Bern, Bern, Switzerland; Graduate School for Cellular and Biomedical Sciences, University of Bern, Bern, Switzerland.
  • 2 Novartis Institutes for BioMedical Research, Basel, Switzerland.
  • 3 Novartis Institutes for BioMedical Research, Cambridge, MA, USA.
  • 4 Proteomics and Mass Spectrometry Core Facility, Department for BioMedical Research, University of Bern, Bern, Switzerland.
  • 5 Department of Chemistry, Biochemistry and Pharmaceutical Sciences, University of Bern, Bern, Switzerland. Electronic address: [email protected].
  • 6 Novartis Institutes for BioMedical Research, Basel, Switzerland. Electronic address: [email protected].
PMID: 37651229 DOI: 10.1016/j.celrep.2023.113056
Abstract

Suppression of premature termination codons (PTCs) by translational readthrough is a promising strategy to treat a wide variety of severe genetic diseases caused by nonsense mutations. Here, we present two potent readthrough promoters-NVS1.1 and NVS2.1-that restore substantial levels of functional full-length CFTR and IDUA proteins in disease models for cystic fibrosis and Hurler syndrome, respectively. In contrast to Other readthrough promoters that affect stop codon decoding, the NVS compounds stimulate PTC suppression by triggering rapid proteasomal degradation of the translation termination factor eRF1. Our results show that this occurs by trapping eRF1 in the terminating ribosome, causing ribosome stalls and subsequent ribosome collisions, and activating a branch of the ribosome-associated quality control network, which involves the translational stress sensor GCN1 and the catalytic activity of the E3 ubiquitin ligases RNF14 and RNF25.

Keywords

CFTR; CP: Molecular biology; E3 ligase; GCN1; Hurler syndrome; IDUA; RNF14; RNF25; RQC; cystic fibrosis; eRF1; proteasomal degradation; readthrough promoter; ribosome collisions; ubiquitination.

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