Mechanisms of readthrough mitigation reveal principles of GCN1-mediated translational quality control

Müller, Martin; Kasturi, Prasad; Jayaraj, Gopal Gunanathan; Hartl, F. Ulrich

doi:10.1016/j.cell.2023.05.035

Cited by 29 publications

(16 citation statements)

References 127 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Another therapeutic option may lie in the inhibition of the quality control machinery that prevents frameshifting and readthrough in human cells, as these systems could possibly detect and eliminate frameshift products. 44 Overall, while our results hint at the potential of using Euplotes eRF1, we believe that multiple approaches, including engineered tRNAs and even small molecules, in combination with a more efficient eRF1 mutant variant could advance this ongoing search for treatment of frameshift mutations and prevent the use of direct genomic interventions.…”

Section: Discussionmentioning

confidence: 67%

Eukaryotic release factor 1 from Euplotes promotes frameshifting at premature stop codons in human cells

Stefanov,

Ajuh,

Allen

et al. 2024

iScience

View full text Add to dashboard Cite

Section: Discussionmentioning

confidence: 67%

Eukaryotic release factor 1 from Euplotes promotes frameshifting at premature stop codons in human cells

Stefanov,

Ajuh,

Allen

et al. 2024

iScience

View full text Add to dashboard Cite

“…Consistent with the idea of an increase in ribosome collisions during viral infection, it was shown that vaccinia virus infection leads to an increase in ubiquitination of the ribosomal protein us10 by the ubiquitin ligase ZNF598, which is known to be directly activated by ribosome collisions (Sundaramoorthy et al, 2021). Alternatively, ribosome collisions could form for other reasons, including the widespread translation of alternative (non-canonical) ORFs that we previously reported (Karasik et al ., 2021), since such ORFs may be less evolutionarily tuned to minimize slow translation (Müller et al, 2023). We also note that ZAKα has been reported to be somewhat activated by individual stalled ribosomes, implying ribosome collisions are not strictly required for the effects observed here (Snieckute et al, 2022).…”

Section: Discussionmentioning

confidence: 99%

Endonucleolytic RNA cleavage drives changes in gene expression during the innate immune response

Karasik,

Lorenzi,

DePass

et al. 2023

Preprint

View full text Add to dashboard Cite

SummaryDuring viral infection, several dsRNA sensors are activated in the cell and trigger signaling that leads to changes in gene expression. One of these sensors activates an endonuclease, RNase L, that cleaves many types of RNA in the cell. However, how the resultant widespread RNA decay affects gene expression is not fully understood. Here we found that gene expression changes caused by activating dsRNA sensing pathways are tuned by RNase L activation, pointing to intricacy in the innate immune response where multiple inputs are integrated to create an optimized output. We show that RNase-L-dependent RNA fragmentation induces the activation of the Ribotoxic Stress Response, potentially through ribosome collisions. The p38 and JNK pathways that are activated as part of this response promote outcomes that inhibit the virus, such as programmed cell death. We also show that RNase L appears to limit the translation of genes that are regulated by another dsRNA-induced pathway, the Integrated Stress Response. Intriguingly, we found the activity of the generic endonuclease, RNase A, recapitulates many of the same molecular phenotypes as activated RNase L, demonstrating how widespread RNA cleavage events can directly evoke an antiviral program.Key summaryActivated RNase L acts together with other dsRNA-sensing pathways to induce a strong immune response via JNK and p38 signalingGeneric RNA fragmentation plays a key role in inducing transcription, potentially through ribosome collisionsActivation of RNase L inhibits the effects of eIF2α phosphorylationTranslation of the antiviral IFIT mRNAs is inhibited by active RNase L

show abstract

“…In terminals (Figure 4B) we found that Gcn1, whose encoded protein enhances translation by removing stalled ribosomes and is associated with polysomes, was strongly upregulated consistent with increased protein synthesis. 44 Other enhanced transcripts included phenol sulfotransferase Sult1a1, 45 whose human homologue is highly inducible by dopamine and is part of a family of proteins thought to protect neurons from neurotoxicity, 46 as well asTmem252 thought to play a possible role in kidney function. 47 Bioinformatic analysis links enhanced glutamatergic synapse activity as well as PI3 Kinase Akt signalling activity with the terminals to NGF -induced enhanced pain statesin agreement with such enhanced activity found in the spinal cord in chronic pain (Figure S6) 48 .…”

Section: Ngf-induced Pain States Alter Translatome Activitymentioning

confidence: 99%

Analgesic targets identified in mouse sensory neuron somata and terminal pain translatomes

Bangash,

Cubuk,

Iseppon

et al. 2024

Preprint

View full text Add to dashboard Cite

The relationship between transcription and protein expression is complex. We identified polysome-associated RNA transcripts in the somata and central terminals of mouse sensory neurons in control, painful (+ Nerve Growth Factor (NGF)) and pain-free conditions (Nav1.7 null mice). The majority (98%) of translated transcripts are shared between male and female mice in both the somata and terminals. Some transcripts are highly enriched in the somata or terminals. Changes in the translatome in painful and pain-free conditions include novel and known regulators of pain pathways. Antisense knockdown of selected somatic and terminal polysome-associated transcripts that correlate with pain states diminished pain behaviour. Terminal-enriched transcripts encoding synaptic proteins (e.g. Synaptotagmin), non-coding RNAs, transcription factors (e.g. Znf431), proteins associated with trans-synaptic trafficking (HoxC9), GABA generating enzymes (Gad1 and Gad2) and neuropeptides (Penk). Thus, central terminal translation may well be a significant regulatory locus for peripheral input from sensory neurons.

show abstract

Mechanisms of readthrough mitigation reveal principles of GCN1-mediated translational quality control

Cited by 29 publications

References 127 publications

Eukaryotic release factor 1 from Euplotes promotes frameshifting at premature stop codons in human cells

Eukaryotic release factor 1 from Euplotes promotes frameshifting at premature stop codons in human cells

Endonucleolytic RNA cleavage drives changes in gene expression during the innate immune response

Analgesic targets identified in mouse sensory neuron somata and terminal pain translatomes

Contact Info

Product

Resources

About