Why the study?
How translation is altered and what in vivo defects arise in the absence of translation-dependent quality control pathways were poorly understood.
Translation-dependent quality control pathways (NGD/NSD/NMD) are critical for cerebellar neurogenesis and embryonic viability in mice, and their absence leads to convergent molecular pathology including ribosome pausing.
Should not yet influence clinical practice; extends mechanistic understanding of translation quality control in embryogenesis while leaving.
Translation-dependent quality control pathways such as no-go decay (NGD), non-stop decay (NSD), and nonsense-mediated decay (NMD) govern protein synthesis and proteostasis by resolving non-translating ribosomes and preventing the production of potentially toxic peptides derived from faulty and aberrant mRNAs. However, how translation is altered and the in vivo defects that arise in the absence of these pathways are poorly understood. Here, we show that the NGD/NSD factors Pelo and Hbs1l are critical in mice for cerebellar neurogenesis but expendable for survival of these neurons after development. Analysis of mutant mouse embryonic fibroblasts revealed translational pauses, alteration of signaling pathways, and translational reprogramming. Similar effects on signaling pathways, including mTOR activation, the translatome and mouse cerebellar development were observed upon deletion of the NMD factor Upf2 . Our data reveal that these quality control pathways that function to mitigate errors at distinct steps in translation can evoke similar cellular responses.
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Terrey et al. (2021) studied this question.
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