Bursting translation on single mRNAs in live cells

Livingston, Nathan M.; Kwon, Jiwoong; Valera, Oliver; Saba, James A.; Sinha, Niladri K.; Reddy, P Krishna Mohan; Nelson, Blake W.; Wolfe, Clara; Ha, Taekjip; Green, Rachel; Liu, Jian; Wu, Bin

doi:10.1016/j.molcel.2023.05.019

Cited by 23 publications

(21 citation statements)

References 92 publications

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“…Eventually, Caf20 may regulate the efficiency of ribosome recruitment, that is, the rate of translation initiation, through a cycle of exchange between eIF4G and Caf20 in the 80S under rapamycin treatment (Figure 5). Recently, it has been reported that mTORC1 adjusts translation bursting (the frequency of translational active state) by phosphorylating 4E-BP (Livingston et al, 2023). This supports our model that transient binding of the yeast 4E-BP modulates translational efficiency in accordance with TORC1 activity.…”

Section: Discussionsupporting

confidence: 90%

Yeast Tor complex 1 phosphorylates eIF4E‐binding protein, Caf20

Kamada,

Ando,

Izawa

et al. 2023

Genes to Cells

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Tor complex 1 (TORC1), a master regulator of cell growth, is an evolutionarily conserved protein kinase within eukaryotic organisms. To control cell growth, TORC1 governs translational processes by phosphorylating its substrate proteins in response to cellular nutritional cues. Mammalian TORC1 (mTORC1) assumes the responsibility of phosphorylating the eukaryotic translation initiation factor 4E (eIF4E)‐binding protein 1 (4E‐BP1) to regulate its interaction with eIF4E. The budding yeast Saccharomyces cerevisiae possesses a pair of 4E‐BP genes, CAF20 and EAP1. However, the extent to which the TORC1‐4E‐BP axis regulates translational initiation in yeast remains uncertain. In this study, we demonstrated the influence of TORC1 on the phosphorylation status of Caf20 in vivo, as well as the direct phosphorylation of Caf20 by TORC1 in vitro. Furthermore, we found the TORC1‐dependent recruitment of Caf20 to the 80S ribosome. Consequently, our study proposes a plausible involvement of yeast's 4E‐BP in the efficacy of translation initiation, an aspect under the control of TORC1.

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Section: Discussionsupporting

confidence: 90%

Yeast Tor complex 1 phosphorylates eIF4E‐binding protein, Caf20

Kamada,

Ando,

Izawa

et al. 2023

Genes to Cells

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“…To determine if transient ribosome collisions also occur during translation of linear mRNAs, we simulated translation of linear mRNAs in which we added a translation initiation step to the computational model. We assumed that the time interval between translation initiation events followed an exponential decay distribution with an average interval of 30 sec (a conservative number based on previous measurements (Livingston et al, 2023; Yan et al ., 2016) and a minimal interval of 10 sec. We then simulated translation on linear mRNAs and determined the frequency of ribosome collisions on mRNAs with different coding sequence lengths (Figures 1K – 1M and Video S3).…”

Section: Resultsmentioning

confidence: 99%

Ribosome cooperativity promotes fast and efficient translation

Madern,

Yang,

Tanenbaum

2024

Preprint

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The genetic information stored in mRNA is decoded by ribosomes during mRNA translation. mRNAs are typically translated by multiple ribosomes simultaneously, but it is unclear if different ribosomes translating the same mRNA functionally interact with each other. Here, we combine single-ribosome imaging and simulations to compare translation dynamics of individual ribosomes in either monosomes or polysomes to determine how ribosomes interact during translation. We find that ribosomes frequently undergo transient collisions, but that transient collisions, unlike persistent collisions, escape detection by cellular quality control pathways. Instead, our results indicate that transient ribosome collisions promote productive translation by suppressing ribosome pausing when ribosomes encounter problems, a process we term ribosome cooperativity. Ribosome cooperativity also suppresses ribosome recycling on problematic sequences, likely by reducing pause duration, thus stimulating processive translation. Together, our results show that ribosomes cooperate during translation to ensure fast and efficient translation.

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“…Specifically, Livingstone et al . 39 , through single-cell mRNA tracking, measured the parameters of translational bursting, and identified the roles of 5’UTR and 5’mRNA cap in modulation of translational burst frequency and burst amplitude.…”

Section: Resultsmentioning

confidence: 99%

Ribosome demand links transcriptional bursts to protein expression noise

Pal,

Ray,

Dhar

2023

Preprint

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Stochastic variation in protein expression generates phenotypic heterogeneity in a cell population, and has important role in antibiotic persistence, mutation penetrance, cancer growth and therapy resistance. Studies investigating molecular origins of noise have predominantly focused on the transcription process. However, the noise generated during the transcription process is further modulated by the translation process, which eventually determines the expression noise at the protein level. Studies across different organisms have revealed a positive correlation between translational efficiency and protein noise. However, the molecular basis of this correlation has remained unknown. In this work, through stochastic modeling of translation in single mRNA molecules and empirical measurement of protein noise, we demonstrate that ribosome demand associated with high translational efficiency drives the correlation between translational efficiency and protein noise. We also show that this correlation is present only in genes with bursty transcription, where ribosome demand varies with stochastic fluctuations in mRNA numbers. Thus, our work reveals how transcriptional bursts are translated into protein noise, which has important implications for investigating protein noise and phenotypic heterogeneity across biological systems.

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Bursting translation on single mRNAs in live cells

Cited by 23 publications

References 92 publications

Yeast Tor complex 1 phosphorylates eIF4E‐binding protein, Caf20

Yeast Tor complex 1 phosphorylates eIF4E‐binding protein, Caf20

Ribosome cooperativity promotes fast and efficient translation

Ribosome demand links transcriptional bursts to protein expression noise

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