Translational Control under Stress: Reshaping the Translatome

Advani, Vivek M.; Ivanov, Pavel

doi:10.1002/bies.201900009

Cited by 149 publications

(109 citation statements)

References 129 publications

(194 reference statements)

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“…This reduces translation of many mRNAs, while selectively enhancing the translation of mRNAs that encode proteins required to cope with the stress, including genes encoding key amino acid biosynthetic enzymes (41). Because P-eIF2α is a competitive inhibitor of eIF2B, and because eIF2α is present in excess of eIF2B, small changes in the levels of P-eIF2α in cells are enough to substantially alter protein synthesis (30,42).…”

Section: Significancementioning

confidence: 99%

Circadian clock control of eIF2α phosphorylation is necessary for rhythmic translation initiation

Karki

Castillo

Ding

et al. 2020

Proc. Natl. Acad. Sci. U.S.A.

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The circadian clock in eukaryotes controls transcriptional and posttranscriptional events, including regulation of the levels and phosphorylation state of translation factors. However, the mechanisms underlying clock control of translation initiation, and the impact of this potential regulation on rhythmic protein synthesis, were not known. We show that inhibitory phosphorylation of eIF2α (P-eIF2α), a conserved translation initiation factor, is clock controlled in Neurospora crassa, peaking during the subjective day. Cycling P-eIF2α levels required rhythmic activation of the eIF2α kinase CPC-3 (the homolog of yeast and mammalian GCN2), and rhythmic activation of CPC-3 was abolished under conditions in which the levels of charged tRNAs were altered. Clock-controlled accumulation of P-eIF2α led to reduced translation during the day in vitro and was necessary for the rhythmic synthesis of select proteins in vivo. Finally, loss of rhythmic P-eIF2α levels led to reduced linear growth rates, supporting the idea that partitioning translation to specific times of day provides a growth advantage to the organism. Together, these results reveal a fundamental mechanism by which the clock regulates rhythmic protein production, and provide key insights into how rhythmic translation, cellular energy, stress, and nutrient metabolism are linked through the levels of charged versus uncharged tRNAs.

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Section: Significancementioning

confidence: 99%

Circadian clock control of eIF2α phosphorylation is necessary for rhythmic translation initiation

Karki

Castillo

Ding

et al. 2020

Proc. Natl. Acad. Sci. U.S.A.

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“…Eukaryotic cells contain ribonucleoprotein (RNP) granules in the nucleus and cytosol, including P-bodies (PBs) and stress granules (SGs) (Anderson and Kedersha, 2006;Banani et al, 2017). Stress granules are cytosolic RNP condensates composed of non-translating mRNPs, which are involved in the stress response, neurodegeneration and viral infection (Protter and Parker, 2016;Advani and Ivanov, 2019). SGs typically form in response to translational shutoff induced by noxious stimuli such as arsenite, heat shock, and endogenous inflammatory molecules like prostaglandins, which all lead to phosphorylation of eIF2α and the activation of the integrated stress response (Aulas et al, 2017;Tauber and Parker, 2019).…”

Section: Introductionmentioning

confidence: 99%

Modulation of RNA condensation by the DEAD-box protein eIF4A

Tauber

Khong

et al. 2019

Preprint

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eTOC Blurb: The RNA helicase eIF4A limits stress granule formation by reducing RNA condensation. Highlights:•! RNA condensates promote intermolecular RNA-RNA interactions at their surfaces! •! eIF4A helicase activity limits the recruitment of RNAs to stress granules in cells! •! eIF4A helicase activity reduces the nucleation of stress granules in cells! •! Recombinant eIF4A1 inhibits the condensation of RNA in vitro in an ATP-dependent manner! Keywords: DEAD-box protein, RNA-RNA interactions, stress granule, ribonucleoprotein ! 2 SUMMARY:Stress granules are condensates of non-translating mRNAs and proteins involved in the stress response and neurodegenerative diseases. Stress granules are proposed to form in part through intermolecular RNA-RNA interactions, although the process of RNA condensation is not well understood. In vitro, we demonstrate that the minimization of surface free energy promotes the recruitment and interaction of RNAs on RNA or RNP condensate surfaces. We demonstrate that the ATPase activity of the DEAD-box RNA helicase eIF4A reduces RNA recruitment to RNA condensates in vitro and in cells, as well as limiting stress granule formation. This defines a new function for eIF4A, and potentially other RNA helicases, to limit thermodynamically favored intermolecular RNA-RNA interactions in cells, thereby allowing for proper RNP function.

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“…How cells regulate translation during adverse stress is key in our understanding of cellular stress pathways and death mechanisms. Over the past decades, our view of tRNA has changed from a static element in the translation complex into a dynamic player in the process of translation regulation 1 . During stress, cells can change tRNA transcripts abundance to drive the translation towards the generation of antioxidant proteins 2 .…”

Section: Introductionmentioning

confidence: 99%

The cell and stress-specific canonical and non-canonical tRNA cleavage

Rashad

Tominaga

Niizuma

2020

Preprint

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Following stress, tRNA is cleaved to generate tRNA halves (tiRNAs). These stress induced small RNAs have been shown to regulate processes such as translation initiation and stem cell function. To date, angiogenin (ANG) is considered the main enzyme that cleaves tRNA at its anti-codon site to generate 35 ~ 45 nucleotide long 5' and 3' tiRNA halves. Herein, using rat model of focal ischemia and 2 different rat neuronal cell lines exposed to different stresses, we show that tRNA cleavage is a selective process that is heterogenous amongst different tRNAs. We also report for the first time the existence of non-canonical tRNA cleavage that is angiogenin independent and that tRNA cleavage is cell specific and stress specific. Moreover, we show that angiogenin-mediated tRNA cleavage itself is tRNA selective and that angiogenin overexpression doesn't lead to the expected overt tRNA cleavage in the cells. Finally, the proposed enzymes responsible for this non-canonical tRNA cleavage do not appear to be regulated by RNH1, the angiogenin inhibitor.

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Translational Control under Stress: Reshaping the Translatome

Cited by 149 publications

References 129 publications

Circadian clock control of eIF2α phosphorylation is necessary for rhythmic translation initiation

Circadian clock control of eIF2α phosphorylation is necessary for rhythmic translation initiation

Modulation of RNA condensation by the DEAD-box protein eIF4A

The cell and stress-specific canonical and non-canonical tRNA cleavage

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