Journal
RNA BIOLOGY
Volume 19, Issue 1, Pages 609-621Publisher
TAYLOR & FRANCIS INC
DOI: 10.1080/15476286.2022.2065116
Keywords
Stress response; UPR; ISR; ribotoxic stress; translation; ribosome; ribosome collisions; quality control; mRNA surveillance; ZNF598; NGD; NSD; NMD; RQC
Categories
Funding
- Novartis Foundation for Biomedical Research
- National Center of Competence in Research (NCCR) on RNA & Disease - Swiss National Science Foundation (SNSF) [51NF40182880]
- SNSF [310030-204161]
- Kanton Bern
- Swiss National Science Foundation (SNF) [310030_204161] Funding Source: Swiss National Science Foundation (SNF)
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Translation problems can activate stress response pathways, and ribosome collisions have emerged as a significant translational stress signal. The E3-ligase ZNF598 plays a crucial role in connecting collided ribosomes with mRNA degradation.
Cells of metazoans respond to internal and external stressors by activating stress response pathways that aim for re-establishing cellular homoeostasis or, if this cannot be achieved, triggering programmed cell death. Problems during translation, arising from defective mRNAs, tRNAs, ribosomes or protein misfolding, can activate stress response pathways as well as mRNA surveillance and ribosome quality control programs. Recently, ribosome collisions have emerged as a central signal for translational stress and shown to elicit different stress responses. Here, we review our current knowledge about the intricate mutual connections between ribosome collisions, stress response pathways and mRNA surveillance. A central factor connecting the sensing of collided ribosomes with degradation of the nascent polypeptides, dissociation of the stalled ribosomes and degradation of the mRNA by no-go or non-stop decay is the E3-ligase ZNF598. We tested whether ZNF598 also plays a role in nonsense-mediated mRNA decay (NMD) but found that it is dispensable for this translation termination-associated mRNA surveillance pathway, which in combination with other recent data argues against stable ribosome stalling at termination codons being the NMD-triggering signal.
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