Translation Initiation from Conserved Non-AUG Codons Provides Additional Layers of Regulation and Coding Capacity

Ivanov, Ivaylo P.; Wei, Jiajie; Caster, Stephen Z.; Smith, Kristina M.; Michel, Audrey M.; Zhang, Ying; Firth, Andrew E.; Freitag, Michael; Dunlap, Jay C.; Bell-Pedersen, Deborah; Atkins, John F.; Sachs, Matthew S.

doi:10.1128/mbio.00844-17

Cited by 30 publications

(39 citation statements)

References 60 publications

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“…We found that multiple near-cognate start codons are used for leaky initiation in Cryptococcus: ACG for the mitochondrial isoform of LeuRS, AUU for the mitochondrial isoform of ArgRS, and the upstream CUG in eIF5. Further work will be needed to quantify the extent of near-cognate start codon usage in Cryptococcus in different growth conditions and compare it to other organisms (14, 72).…”

Section: Discussionmentioning

confidence: 99%

“…N. crassa (strain OR74A) ribosome profiling data from ((14), GEO:GSE97717) was used to generate highly-translated genes, and ribosome profiling and RNA-seq data from ((98), GEO: GSE71032) used to estimated TE. In both cases, we estimated TPMs using the RiboViz pipeline as above, using the NC12 genome annotation downloaded from EnsembIGenomes (99).…”

Section: Methodsmentioning

confidence: 99%

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Start codon context controls translation initiation in the fungal kingdom

Wallace

Maufrais

Sales-Lee

et al. 2019

Preprint

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Eukaryotic protein synthesis initiates at a start codon defined by an AUG and its surrounding Kozak sequence context, but studies of S. cerevisiae suggest this context is of little importance in fungi. We tested this concept in two pathogenic Cryptococcus species by genome-wide mapping of translation and of mRNA 5’ and 3’ ends. We observed that upstream open reading frames (uORFs) are a major contributor to translation repression, that uORF use depends on the Kozak sequence context of its start codon, and that uORFs with strong contexts promote nonsense-mediated mRNA decay. Numerous Cryptococcus mRNAs encode predicted dual-localized proteins, including many aminoacyl-tRNA synthetases, in which a leaky AUG start codon is followed by a strong Kozak context in-frame AUG, separated by mitochondrial-targeting sequence. Further analysis shows that such dual-localization is also predicted to be common in Neurospora crassa. Kozak-controlled regulation is correlated with insertions in translational initiation factors in fidelity-determining regions that contact the initiator tRNA. Thus, start codon context is a signal that programs the expression and structures of proteins in fungi.

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Section: Discussionmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

Start codon context controls translation initiation in the fungal kingdom

Wallace

Maufrais

Sales-Lee

et al. 2019

Preprint

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“…As non-AUG initiation events are influenced by both the translation machinery and the mRNA sequence/ structure, an intriguing question is whether we can accurately predict non-AUG translation events in any given transcript. In silico tools using algorithms that are based on ribosome profiling data sets are now available to help predict true non-AUG start codons (Reuter et al 2016), and the inclusion of additional data, including secondary structure predictions (Kochetov et al 2007) and evolutionary conservation (Ivanov et al 2011(Ivanov et al , 2017, likely can improve accuracy. However, as noted in the multiple examples that were highlighted throughout this review, cellular conditions (e.g., stress) and disease mutations significantly influence start codon usage.…”

Section: Perspectives and Concluding Remarksmentioning

confidence: 99%

Non-AUG translation: a new start for protein synthesis in eukaryotes

2017

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Although it was long thought that eukaryotic translation almost always initiates at an AUG start codon, recent advancements in ribosome footprint mapping have revealed that non-AUG start codons are used at an astonishing frequency. These non-AUG initiation events are not simply errors but instead are used to generate or regulate proteins with key cellular functions; for example, during development or stress. Misregulation of non-AUG initiation events contributes to multiple human diseases, including cancer and neurodegeneration, and modulation of non-AUG usage may represent a novel therapeutic strategy. It is thus becoming increasingly clear that start codon selection is regulated by many -acting initiation factors as well as sequence/structural elements within messenger RNAs and that non-AUG translation has a profound impact on cellular states.

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“…CPC-1 is the master transcription regulator of gene expression in Neurospora in response to amino acid starvation (3,7,55,62). Like the situation of its yeast ortholog GCN4, the expression of CPC-1 is also translationally regulated by a mechanism involving uORFs (7,9).…”

Section: Discussionmentioning

confidence: 99%

Non-optimal codon usage is critical for protein structure and function of the master general amino acid control regulator CPC-1

Lyu

Liu

2020

Preprint

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Under amino acid starvation condition, eukaryotic organisms activate a general amino acid control response. In Neurospora crassa, Cross Pathway Control-1 (CPC-1), the ortholog of the Saccharomyces cerevisiae bZIP transcription factor GCN4, functions as the master regulator of the general amino acid control response. Codon usage biases are a universal feature of eukaryotic genomes and are critical for regulation of gene expression. Although codon usage has also been implicated in the regulation of protein structure and function, genetic evidence supporting this conclusion is very limited. Here we show that Neurospora cpc-1 has a non-optimal NNU-rich codon usage profile that contrasts with the strong NNC codon preference in the genome. Although substitution of the cpc-1 NNU codons with synonymous NNC codons elevated CPC-1 expression in Neurospora, it altered CPC-1 degradation rate and abolished its amino acid starvation-induced protein stabilization. The codon-manipulated CPC-1 protein also exhibited different sensitivity to limited protease digestion. Furthermore, CPC-1 functions in rescuing the cell growth of the cpc-1 deletion mutant and activating the expression of its target genes were impaired by the synonymous codon changes. Together, these results reveal the critical role of codon usage in regulating of CPC-1 expression and function, and establish a genetic example of the importance of codon usage in protein structure.

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Translation Initiation from Conserved Non-AUG Codons Provides Additional Layers of Regulation and Coding Capacity

Cited by 30 publications

References 60 publications

Start codon context controls translation initiation in the fungal kingdom

Start codon context controls translation initiation in the fungal kingdom

Non-AUG translation: a new start for protein synthesis in eukaryotes

Non-optimal codon usage is critical for protein structure and function of the master general amino acid control regulator CPC-1

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