eIF2A, an initiator tRNA carrier refractory to eIF2α kinases, functions synergistically with eIF5B

Kim, Eunah; Kim, Joon Hyun; Seo, Keunhee; Hong, Ka Young; An, Seon Woo A.; Kwon, Jun-Young; Lee, Seung-Jae; Jang, Sung Key

doi:10.1007/s00018-018-2870-4

Cited by 35 publications

(48 citation statements)

References 61 publications

(78 reference statements)

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“…The same eIF2D was described to facilitate HCV translation initiation [187]. According to a recent study [186], eIF2A can also function synergistically with eIF5B. Both eIF2A and eIF5B can bind to the 40S subunit during stress conditions [186].…”

Section: Use Of Alternative Initiation Factors Under Stress Conditionsmentioning

confidence: 93%

“…Then, translation initiation at the HCV IRES is mediated by alternative initiation factors. Several protein factors have been proposed for this role including eIF2A [184], eIF2D [183], eIF5B [185], a combination of eIF2A and eIF5B [186], and the complex of the proteins MCT-1 and DENR [187]. The 139 kDa eIF5B (the eukaryotic homolog of bacterial IF2) [188,189] can promote formation of 80S complexes with the HCV IRES initiator-tRNA binding to the ribosomal P site in the presence of only additional eIF3 [51,149,185] (Figure 5B).…”

Section: Use Of Alternative Initiation Factors Under Stress Conditionsmentioning

confidence: 99%

“…Meanwhile, there are conflicting reports about the possible role of eIF2A. Cloned eIF2A (NCBI nucleotide database entry NM_032025) has been described to have Met-tRNA binding properties and is also able to deliver Met-tRNA i Met in HCV translation initiation [184,186]. This eIF2A interacts with the HCV IRES core domain including SLs IIId, IIIe, IIIf, and the pseudoknots, with specific binding determinants present in the SL IIId, and eIF2A relocates from the nucleus to the cytoplasm in HCV-infected cells [184], suggesting its importance to function as an eIF2 surrogate during HCV infection under stress conditions.…”

Section: Use Of Alternative Initiation Factors Under Stress Conditionsmentioning

confidence: 99%

“…According to a recent study [186], eIF2A can also function synergistically with eIF5B. Both eIF2A and eIF5B can bind to the 40S subunit during stress conditions [186]. eIF5B interacts both with eIF2A and with the tRNA, and eIF5B augments the activity of eIF2A in loading Met-tRNA i Met onto a 40S ribosome associated with an HCV [186].…”

Section: Use Of Alternative Initiation Factors Under Stress Conditionsmentioning

confidence: 99%

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Hepatitis C Virus Translation Regulation

Niepmann

Gerresheim

2020

IJMS

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Translation of the hepatitis C virus (HCV) RNA genome is regulated by the internal ribosome entry site (IRES), located in the 5’-untranslated region (5′UTR) and part of the core protein coding sequence, and by the 3′UTR. The 5′UTR has some highly conserved structural regions, while others can assume different conformations. The IRES can bind to the ribosomal 40S subunit with high affinity without any other factors. Nevertheless, IRES activity is modulated by additional cis sequences in the viral genome, including the 3′UTR and the cis-acting replication element (CRE). Canonical translation initiation factors (eIFs) are involved in HCV translation initiation, including eIF3, eIF2, eIF1A, eIF5, and eIF5B. Alternatively, under stress conditions and limited eIF2-Met-tRNAiMet availability, alternative initiation factors such as eIF2D, eIF2A, and eIF5B can substitute for eIF2 to allow HCV translation even when cellular mRNA translation is downregulated. In addition, several IRES trans-acting factors (ITAFs) modulate IRES activity by building large networks of RNA-protein and protein–protein interactions, also connecting 5′- and 3′-ends of the viral RNA. Moreover, some ITAFs can act as RNA chaperones that help to position the viral AUG start codon in the ribosomal 40S subunit entry channel. Finally, the liver-specific microRNA-122 (miR-122) stimulates HCV IRES-dependent translation, most likely by stabilizing a certain structure of the IRES that is required for initiation.

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Section: Use Of Alternative Initiation Factors Under Stress Conditionsmentioning

confidence: 93%

Section: Use Of Alternative Initiation Factors Under Stress Conditionsmentioning

confidence: 99%

Section: Use Of Alternative Initiation Factors Under Stress Conditionsmentioning

confidence: 99%

Section: Use Of Alternative Initiation Factors Under Stress Conditionsmentioning

confidence: 99%

See 2 more Smart Citations

Hepatitis C Virus Translation Regulation

Niepmann

Gerresheim

2020

IJMS

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“…Ã indicates significant enrichment (P , 0.05; hypergeometric enrichment test). phosph-eIF2a, a marker of cellular stress (Kim et al 2018;Kulalert et al 2017;Taniuchi et al 2016;Pakos-Zebrucka et al 2016). This was indeed the case, and excess 5-HT caused a time-dependent increase in the levels of phosphorylated eIFa ( Figure 5D).…”

Section: Resultsmentioning

confidence: 53%

Global Transcriptome Changes That Accompany Alterations in Serotonin Levels inCaenorhabditis elegans

Cruz-Corchado¹,

Ooi²,

Das³

et al. 2020

G3 Genes|Genomes|Genetics

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Serotonin (5-hydroxytryptamine, 5-HT), is a phylogenetically ancient molecule best characterized as a neurotransmitter that modulates multiple aspects of mood and social cognition. The roles that 5-HT plays in normal and abnormal behavior are not fully understood but have been posited to be due to its common function as a ‘defense signal’. However, 5-HT levels also systemically impact cell physiology, modulating cell division, migration, apoptosis, mitochondrial biogenesis, cellular metabolism and differentiation. Whether these diverse cellular effects of 5-HT also share a common basis is unclear. C. elegans provides an ideal system to interrogate the systemic effects of 5-HT, since lacking a blood-brain barrier, 5-HT synthesized and released by neurons permeates the organism to modulate neuronal as well as non-neuronal cells throughout the body. Here we used RNA-Seq to characterize the systemic changes in gene expression that occur in C. elegans upon altering 5-HT levels, and compared the transcriptomes to published datasets. We find that an acute increase in 5-HT is accompanied by a global decrease in gene expression levels, upregulation of genes involved in stress pathways, changes that significantly correlate with the published transcriptomes of animals that have activated defense and immune responses, and an increase in levels of phosphorylated eukaryotic initiation factor, eIF2α. In 5-HT deficient animals lacking tryptophan hydroxylase (tph-1(mg280) II) there is a net increase in gene expression, with an overrepresentation of genes related to development and chromatin. Surprisingly, the transcriptomes of animals with acute increases in 5-HT levels, and 5-HT deficiency do not overlap with transcriptomes of mutants with whom they share striking physiological resemblance. These studies are the first to catalog systemic transcriptome changes that occur upon alterations in 5-HT levels. They further show that in C. elegans changes in gene expression upon altering 5-HT levels, and changes in physiology, are not directly correlated.

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Unconventional translation initiation factor EIF2A is required for Drosophila spermatogenesis

Lowe

Montell

2021

Developmental Dynamics

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Background: EIF2A is an unconventional translation factor required for initiation of protein synthesis from non-AUG codons from a variety of transcripts, including oncogenes and stress related transcripts in mammalian cells. Its function in multicellular organisms has not been reported. Results: Here, we identify and characterize mutant alleles of the CG7414 gene, which encodes the Drosophila EIF2A ortholog. We identified that CG7414 undergoes sex-specific splicing that regulates its male-specific expression. We characterized a Mi{Mic} transposon insertion that disrupts the coding regions of all predicted isoforms and is a likely null allele, and a PBac transposon insertion into an intron, which is a hypomorph. The Mi{Mic} allele is homozygous lethal, while the viable progeny from the hypomorphic PiggyBac allele are male sterile and female fertile. In dEIF2A mutant flies, sperm failed to individualize due to defects in F-actin cones and failure to form and maintain cystic bulges, ultimately leading to sterility. Conclusions: These results demonstrate that EIF2A is essential in a multicellular organism, both for normal development and spermatogenesis, and provide an entrée into the elucidation of the role of EIF2A and unconventional translation in vivo.

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eIF2A, an initiator tRNA carrier refractory to eIF2α kinases, functions synergistically with eIF5B

Cited by 35 publications

References 61 publications

Hepatitis C Virus Translation Regulation

Hepatitis C Virus Translation Regulation

Global Transcriptome Changes That Accompany Alterations in Serotonin Levels inCaenorhabditis elegans

Unconventional translation initiation factor EIF2A is required for Drosophila spermatogenesis

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