eIF5

Jennings, Martin D.; Pavitt, Graham D.

doi:10.4161/sgtp.1.2.13783

Cited by 26 publications

(12 citation statements)

References 53 publications

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“…The molecular mechanisms of this phenomenon remains poorly understood. We observed ~3-fold attenuation of mRNA encoding eukaryotic translation initiation factor 5 (eIF5) (Table 3, see Supplementary Table S4) playing an ubiquitous role in protein synthesis by triggering GTP hydrolysis and mRNA translation2526.…”

Section: Resultsmentioning

confidence: 99%

Time- and dose dependent actions of cardiotonic steroids on transcriptome and intracellular content of Na+ and K+: a comparative analysis

Климанова

Tverskoi

Кольцова

et al. 2017

Sci Rep

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Recent studies demonstrated that in addition to Na+,K+-ATPase inhibition cardiotonic steroids (CTSs) affect diverse intracellular signaling pathways. This study examines the relative impact of [Na+]i/[K+]i-mediated and -independent signaling in transcriptomic changes triggered by the endogenous CTSs ouabain and marinobufagenin (MBG) in human umbilical vein endothelial cells (HUVEC). We noted that prolongation of incubation increased the apparent affinity for ouabain estimated by the loss of [K+]i and gain of [Na+]i. Six hour exposure of HUVEC to 100 and 3,000 nM ouabain resulted in elevation of the [Na+]i/[K+]i ratio by ~15 and 80-fold and differential expression of 258 and 2185 transcripts, respectively. Neither [Na+]i/[K+]i ratio nor transcriptome were affected by 6-h incubation with 30 nM ouabain. The 96-h incubation with 3 nM ouabain or 30 nM MBG elevated the [Na+]i/[K+]i ratio by ~14 and 3-fold and led to differential expression of 880 and 484 transcripts, respectively. These parameters were not changed after 96-h incubation with 1 nM ouabain or 10 nM MBG. Thus, our results demonstrate that elevation of the [Na+]i/[K+]i ratio is an obligatory step for transcriptomic changes evoked by CTS in HUVEC. The molecular origin of upstream [Na+]i/[K+]i sensors involved in transcription regulation should be identified in forthcoming studies.

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Section: Resultsmentioning

confidence: 99%

Time- and dose dependent actions of cardiotonic steroids on transcriptome and intracellular content of Na+ and K+: a comparative analysis

Климанова

Tverskoi

Кольцова

et al. 2017

Sci Rep

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“…eIF5 is composed of two structured domains joined by an LR (62). There are separate structures for the amino terminal GAP domain and a CTD.…”

Section: Discussionmentioning

confidence: 99%

eIF2β is critical for eIF5-mediated GDP-dissociation inhibitor activity and translational control

Jennings¹,

Kershaw²,

White³

et al. 2016

Nucleic Acids Res

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In protein synthesis translation factor eIF2 binds initiator tRNA to ribosomes and facilitates start codon selection. eIF2 GDP/GTP status is regulated by eIF5 (GAP and GDI functions) and eIF2B (GEF and GDF activities), while eIF2α phosphorylation in response to diverse signals is a major point of translational control. Here we characterize a growth suppressor mutation in eIF2β that prevents eIF5 GDI and alters cellular responses to reduced eIF2B activity, including control of GCN4 translation. By monitoring the binding of fluorescent nucleotides and initiator tRNA to purified eIF2 we show that the eIF2β mutation does not affect intrinsic eIF2 affinities for these ligands, neither does it interfere with eIF2 binding to 43S pre-initiation complex components. Instead we show that the eIF2β mutation prevents eIF5 GDI stabilizing nucleotide binding to eIF2, thereby altering the off-rate of GDP from eIF2•GDP/eIF5 complexes. This enables cells to grow with reduced eIF2B GEF activity but impairs activation of GCN4 targets in response to amino acid starvation. These findings provide support for the importance of eIF5 GDI activity in vivo and demonstrate that eIF2β acts in concert with eIF5 to prevent premature release of GDP from eIF2γ and thereby ensure tight control of protein synthesis initiation.

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“…Indeed eIF5 may change position within the complex between scanning and AUG recognition steps prior to its release from initiating ribosomes with eIF2-GDP (Obayashi et al, 2017). eIF5 binds to both eIF2β and γ subunits (Alone & Dever, 2006;Asano, Krishnamoorthy, Phan, Pavitt, & Hinnebusch, 1999;Das, Maiti, Das, & Maitra, 1997;Jennings & Pavitt, 2010a) and with equal affinity for both eIF2-GDP and TC forms (Algire et al, 2005) (Figure 3b). Hence eIF2-GDP is released from the PIC in complex with eIF5 (Singh et al, 2006) Although eIF2 binds GDP more tightly than GTP (Erickson & Hannig, 1996;Jennings et al, 2016), eIF5 further enhances the affinity of yeast eIF2 for GDP and therefore prevents premature eIF2B-independent release of GDP from eIF2γ (Jennings et al, 2016;Jennings & Pavitt, 2010b).…”

Section: Eif5mentioning

confidence: 99%

“…This could occur before, concurrently with eIF2α binding to eIF2B, or immediately following it ( Figure 5, steps 2 and 8). As 2Bε GEF and eIF5 CTD share similar structures (Bieniossek et al, 2006;Boesen et al, 2004;Wei, Xue, Xu, & Gong, 2006) and eIF2βγ binding sites (Alone & Dever, 2006;Asano et al, 1999;Das et al, 1997;Jennings & Pavitt, 2010a), hence eIF5 likely occupies a position on eIF2 that would prevent productive 2Bε GEF interaction. While eIF5-binding to eIF2 can stabilize GDP binding (GDI activity), 2Bε GEF has the opposite impact and facilitates rapid GDP release (Jennings et al, 2013) (step 3).…”

Section: Eif5 Release and Guanine Nucleotide Exchangementioning

confidence: 99%

Regulation of translation initiation factor eIF2B at the hub of the integrated stress response

Pavitt

2018

WIREs RNA

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Phosphorylation of the translation initiation factor eIF2 is one of the most widely used and well-studied mechanisms cells use to respond to diverse cellular stresses. Known as the integrated stress response (ISR), the control pathway uses modulation of protein synthesis to reprogram gene expression and restore homeostasis. Here the current knowledge of the molecular mechanisms of eIF2 activation and its control by phosphorylation at a single-conserved phosphorylation site, serine 51 are discussed with a major focus on the regulatory roles of eIF2B and eIF5 where a current molecular view of ISR control of eIF2B activity is presented. How genetic disorders affect eIF2 or eIF2B is discussed, as are syndromes where excess signaling through the ISR is a component. Finally, studies into the action of recently identified compounds that modulate the ISR in experimental systems are discussed; these suggest that eIF2B is a potential therapeutic target for a wide range of conditions. This article is categorized under: Translation > Translation Regulation.

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eIF5

Cited by 26 publications

References 53 publications

Time- and dose dependent actions of cardiotonic steroids on transcriptome and intracellular content of Na+ and K+: a comparative analysis

Time- and dose dependent actions of cardiotonic steroids on transcriptome and intracellular content of Na+ and K+: a comparative analysis

eIF2β is critical for eIF5-mediated GDP-dissociation inhibitor activity and translational control

Regulation of translation initiation factor eIF2B at the hub of the integrated stress response

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