Surviving and Adapting to Stress: Translational Control and the Integrated Stress Response

Wek, Ronald C.; Anthony, Tracy G.; Staschke, Kirk A.

doi:10.1089/ars.2022.0123

Cited by 25 publications

(22 citation statements)

References 214 publications

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“…The eIF4F complex is a major regulator of translation initiation linked to nutrient sensing, stress adaptation, cell differentiation, and organismal development (4,13,19).…”

Section: Discussionmentioning

confidence: 99%

“…Multiple lines of research involving model organisms have suggested that the translation of some mRNAs is more sensitive to eIF4E1 levels than others (4,13,19).…”

Section: Depletion Of Eif4e1 Reduces Translation and Replicationmentioning

confidence: 99%

“…As stress has long been known to convert tachyzoites to bradyzoites (1, 2), we initiated studies of stress-induced translational control in Toxoplasma (3). The stress-dependent phosphorylation of the alpha subunit of eukaryotic initiation factor-2 (eIF2α) deters the delivery of initiator tRNA to ribosomes, abrogating appropriate start codon recognition and efficiency (4). Consequently, global protein synthesis is curtailed while favoring the selective translation of mRNAs encoding factors that drive an adaptive response.…”

Section: Introductionmentioning

confidence: 99%

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mRNA cap-binding protein eIF4E1 is a novel regulator ofToxoplasma gondiilatency

Holmes,

Bastos,

Dey

et al. 2023

Preprint

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The protozoan parasiteToxoplasma gondiicauses serious opportunistic disease due to its ability to persist in patients as latent tissue cysts. The molecular mechanisms coordinating conversion between proliferative parasites (tachyzoites) and dormant cysts (bradyzoites) are not fully understood. We previously showed that phosphorylation of eIF2α accompanies bradyzoite formation, suggesting that this clinically relevant process involves regulation of mRNA translation. In this study, we investigated the composition and role of eIF4F multi-subunit complexes in translational control. Using CLIPseq, we find that the cap-binding subunit, eIF4E1, localizes to the 5’-end of all tachyzoite mRNAs, many of which show evidence of stemming from heterogenous transcriptional start sites. We further show that eIF4E1 operates as the predominant cap-binding protein in two distinct eIF4F complexes. Using genetic and pharmacological approaches, we found that eIF4E1 deficiency triggers efficient spontaneous formation of bradyzoites without stress induction. Consistent with this result, we also show that stress-induced bradyzoites exhibit reduced eIF4E1 expression. Overall, our findings establish a novel role for eIF4F in translational control required for parasite latency and microbial persistence.SignificanceToxoplasma gondiiis an opportunistic pathogen of importance to global human and animal health. There are currently no chemotherapies targeting the encysted form of the parasite. Consequently, a better understanding of the mechanisms controlling encystation are required. Here we show that the mRNA cap-binding protein, eIF4E1, is involved in regulating the encystation process. Encysted parasites reduce eIF4E1 levels and depletion of eIF4E1 decreases the translation of ribosome-associated machinery and drivesToxoplasmaencystation. Together, these data reveal a new layer of mRNA translational control that regulates parasite encystation and latency.

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“…The eIF4F complex is a major regulator of translation initiation linked to nutrient sensing, stress adaptation, cell differentiation, and organismal development (4,13,19).…”

Section: Discussionmentioning

confidence: 99%

“…Multiple lines of research involving model organisms have suggested that the translation of some mRNAs is more sensitive to eIF4E1 levels than others (4,13,19).…”

Section: Depletion Of Eif4e1 Reduces Translation and Replicationmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

mRNA cap-binding protein eIF4E1 is a novel regulator ofToxoplasma gondiilatency

Holmes,

Bastos,

Dey

et al. 2023

Preprint

Self Cite

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show abstract

“…In response to chemical or physical stress, organisms activate a variety of processes, including quality control mechanisms that preserve the integrity of biological molecules as well as stress response pathways enabling them to mitigate the effect of damage. Shared among all organisms is also their ability to quickly reprogram gene expression to adapt and/or to survive changing environmental conditions ( 2 , 3 , 4 , 5 , 6 , 7 , 8 , 9 ).…”

mentioning

confidence: 99%

“…For example, in response to nutrient availability, the TOR (target of rapamycin) pathway phosphorylates several translation factors and ribosomal proteins, which in turn promote protein synthesis ( 1 ). Conversely, in response to stress, the integrated stress response (ISR) is activated leading to inhibition of protein synthesis ( 5 ). Remarkably, in addition to being a target of these pathways, the ribosome has recently emerged as a central sensor for them.…”

mentioning

confidence: 99%