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

Abstract

Suppression of premature termination codons (PTC) by translational readthrough is a promising strategy to treat a wide variety of severe genetic diseases caused by nonsense mutations. Here, we present two novel and 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, activating a novel branch of the ribosome-associated quality control (RQC) network that involves the translational stress sensor GCN1 and the catalytic activity of the E3 ubiquitin ligases RNF14 and RNF25.

Is there a localized role for translational quality control?

“…In addition, the ubiquitin ligases RNF14 (Itt1 in yeast) and RNF25 bind to collided ribosomes with GCN1 and ubiquitinate (leading to degradation of) the proteins eEF1A (Oltion et al 2023) or eRF1 (Gurzeler et al 2023;Oltion et al 2023). Degradation of these proteins can be induced with a particular natural product or synthetic compounds, but the physiological signals that trigger this pathway remain unknown.…”

“…Ubiquitination of eEF1A and eRF1 to promote their degradation (Urakov et al 2001;Gurzeler et al 2023;Oltion et al 2023) Cold…”