Repression of ferritin light chain translation by human eIF3

AbstractA central problem in human biology remains the discovery of causal molecular links between mutations identified in genome-wide association studies (GWAS) and their corresponding disease traits. This challenge is magnified for variants residing in non-coding regions of the genome. Single-nucleotide polymorphisms (SNPs) in the 5’ untranslated region (5’-UTR) of the ferritin light chain (FTL) gene that cause hyperferritinemia are thought to disrupt translation repression by altering iron regulatory protein (IRP) interactions with theFTLmRNA 5’-UTR. Here, we show that human eukaryotic translation initiation factor 3 (eIF3) acts as a distinct repressor ofFTLmRNA translation, and eIF3-mediatedFTLrepression is disrupted by a subset of SNPs inFTLthat cause hyperferritinemia. These results identify a direct role for eIF3-mediated translational control in a specific human disease.

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Repression of ferritin light chain translation by human eIF3

eLife ◽

10.7554/elife.48193 ◽

2019 ◽

Vol 8 ◽

Cited By ~ 4

Author(s):

Mia C Pulos-Holmes ◽

Daniel N Srole ◽

Maria G Juarez ◽

Amy S-Y Lee ◽

David T McSwiggen ◽

...

Keyword(s):

Light Chain ◽

Translational Control ◽

Association Studies ◽

Regulatory Protein ◽

Mrna Translation ◽

Translation Initiation Factor ◽

Initiation Factor ◽

Genome Wide Association Studies ◽

Nucleotide Polymorphisms ◽

Direct Role

A central problem in human biology remains the discovery of causal molecular links between mutations identified in genome-wide association studies (GWAS) and their corresponding disease traits. This challenge is magnified for variants residing in non-coding regions of the genome. Single-nucleotide polymorphisms (SNPs) in the 5ʹ untranslated region (5ʹ-UTR) of the ferritin light chain (FTL) gene that cause hyperferritinemia are reported to disrupt translation repression by altering iron regulatory protein (IRP) interactions with the FTL mRNA 5ʹ-UTR. Here, we show that human eukaryotic translation initiation factor 3 (eIF3) acts as a distinct repressor of FTL mRNA translation, and eIF3-mediated FTL repression is disrupted by a subset of SNPs in FTL that cause hyperferritinemia. These results identify a direct role for eIF3-mediated translational control in a specific human disease.

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Identification of GCD14 and GCD15, Novel Genes Required for Translational Repression of GCN4 mRNA in Saccharomyces cerevisiae

Genetics ◽

10.1093/genetics/148.3.1007 ◽

1998 ◽

Vol 148 (3) ◽

pp. 1007-1020 ◽

Cited By ~ 2

Author(s):

Rafael Cuesta ◽

Alan G Hinnebusch ◽

Mercedes Tamame

Keyword(s):

Saccharomyces Cerevisiae ◽

Amino Acid ◽

Translation Initiation ◽

Translational Control ◽

Mrna Translation ◽

Translation Initiation Factor ◽

Initiation Factor ◽

Mrna Levels ◽

New Genes ◽

General Translation

Abstract In Saccharomyces cerevisiae, expression of the transcriptional activator GCN4 increases at the translational level in response to starvation for an amino acid. The products of multiple GCD genes are required for efficient repression of GCN4 mRNA translation under nonstarvation conditions. The majority of the known GCD genes encode subunits of the general translation initiation factor eIF-2 or eIF-2B. To identify additional initiation factors in yeast, we characterized 65 spontaneously arising Gcd− mutants. In addition to the mutations that were complemented by known GCD genes or by GCN3, we isolated mutant alleles of two new genes named GCD14 and GCD15. Recessive mutations in these two genes led to highly unregulated GCN4 expression and to derepressed transcription of genes in the histidine biosynthetic pathway under GCN4 control. The derepression of GCN4 expression in gcd14 and gcd15 mutants occurred with little or no increase in GCN4 mRNA levels, and it was dependent on upstream open reading frames (uORFs) in GCN4 mRNA that regulate its translation. We conclude that GCD14 and GCD15 are required for repression of GCN4 mRNA translation by the uORFs under conditions of amino acid sufficiency. The gcd14 and gcd15 mutations confer a slow-growth phenotype on nutrient-rich medium, and gcd15 mutations are lethal when combined with a mutation in gcd13. Like other known GCD genes, GCD14 and GCD15 are therefore probably required for general translation initiation in addition to their roles in GCN4-specific translational control.

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Distinct domains of Me31B interact with different eIF4E isoforms in the male germ line of Drosophila melanogaster

10.1101/2021.03.23.436655 ◽

2021 ◽

Author(s):

Carla Layana ◽

Emiliano S. Vilardo ◽

Gonzalo Corujo ◽

Greco Hernandez ◽

Rolando Rivera-Pomar

Keyword(s):

Drosophila Melanogaster ◽

Translational Control ◽

Germ Line ◽

Mrna Translation ◽

Translation Initiation Factor ◽

Initiation Factor ◽

Interacting Protein ◽

Control Of Gene Expression ◽

Amino Terminal ◽

Key Factor

Eukaryotic translation initiation factor 4E (eIF4E) is a key factor involved in different aspects of mRNA metabolism. Drosophila melanogaster genome encodes eight eIF4E isoforms, and the canonical isoform eIF4E-1 is a ubiquitous protein that plays a key role in mRNA translation. eIF4E-3 is specifically expressed in testis and controls translation during spermatogenesis. In eukaryotic cells, translational control and mRNA decay is highly regulated in different cytoplasmic ribonucleoprotein foci, which include the processing bodies (PBs). In this study, we show that Drosophila eIF4E-1 and eIF4E-3 occur in PBs where might play a role in mRNA storage and translational repression. We also demonstrate that the DEAD-box RNA helicase Me31B, a component of PBs, physically interacts with eIF4E-1 and eIF4E-3 both in the yeast two-hybrid system and FRET in Drosophila S2 cells. Moreover, truncated and point mutated Me31B proteins indicate that the binding sites of Me31B for eIF4E-1 and eIF4E-3 are located in different domains. Residues Y401-L407 (at the carboxy-terminal) are essential for interaction with eIF4E-1, whereas residues F63-L70 (at the amino-terminal) are critical for interaction with eIF4E-3. Thus, Me31B represents a novel type of eIF4E-interacting protein. Our observations suggest that Me31B might recognize different eIF4E isoforms in different tissues, which could be the key to silencing specific messengers. They provide further evidence that alternative forms of eIF4E and their interactions with various partners add complexity to the control of gene expression in eukaryotes.

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A point mutation in the nucleotide exchange factor eIF2B constitutively activates the integrated stress response by allosteric modulation

10.1101/2021.12.03.471181 ◽

2021 ◽

Author(s):

Lan Wang ◽

Morgane Boone ◽

Rosalie E Lawrence ◽

Adam Frost ◽

Peter Walter ◽

...

Keyword(s):

Stress Response ◽

Point Mutation ◽

Translational Control ◽

Mrna Translation ◽

Translation Initiation Factor ◽

Initiation Factor ◽

Integrated Stress Response ◽

Nucleotide Exchange ◽

Exchange Factor ◽

Nucleotide Exchange Factor

AbstractIn eukaryotic cells, stressors reprogram the cellular proteome by activating the integrated stress response (ISR). In its canonical form, stress-sensing kinases phosphorylate the eukaryotic translation initiation factor eIF2 (eIF2-P), which ultimately leads to reduced levels of ternary complex required for initiation of mRNA translation. Translational control is primarily exerted through a conformational switch in eIF2’s nucleotide exchange factor, eIF2B, which shifts from its active A-State conformation to its inhibited I-State conformation upon eIF2-P binding, resulting in reduced nucleotide exchange on eIF2. Here, we show functionally and structurally how a single histidine to aspartate point mutation in eIF2B’s β subunit (H160D) mimics the effects of eIF2-P binding by promoting an I-State like conformation, resulting in eIF2-P independent activation of the ISR. These findings corroborate our previously proposed (Schoof et al. 2021) A/I-State model of allosteric ISR regulation.

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Eukaryotic Translation Initiation Factor 5 Is Critical for Integrity of the Scanning Preinitiation Complex and Accurate Control of GCN4 Translation

Molecular and Cellular Biology ◽

10.1128/mcb.25.13.5480-5491.2005 ◽

2005 ◽

Vol 25 (13) ◽

pp. 5480-5491 ◽

Cited By ~ 36

Author(s):

Chingakham Ranjit Singh ◽

Cynthia Curtis ◽

Yasufumi Yamamoto ◽

Nathan S. Hall ◽

Dustin S. Kruse ◽

...

Keyword(s):

Amino Acid ◽

Translation Initiation ◽

Translational Control ◽

Point Mutations ◽

Mrna Translation ◽

Translation Initiation Factor ◽

Initiation Factor ◽

Preinitiation Complex ◽

Eukaryotic Translation ◽

Eukaryotic Translation Initiation

ABSTRACT The integrity of eukaryotic translation initiation factor (eIF) interactions in ribosomal preinitiation complexes is critical for the proper regulation of GCN4 mRNA translation in response to amino acid availability. Increased phosphorylation of eIF2 under amino acid starvation conditions leads to a corresponding increase in GCN4 mRNA translation. The carboxyl-terminal domain (CTD) of eIF5 (eIF5-CTD) has been identified as a potential nucleation site for preinitiation complex assembly. To further characterize eIF5 and delineate its role in GCN4 translational control, we isolated mutations leading to temperature sensitivity (Ts− phenotype) targeted at TIF5, the structural gene encoding eIF5 in yeast (Saccharomyces cerevisiae). Nine single point mutations were isolated, in addition to an allele in which the last 15 amino acids were deleted. The nine point mutations clustered in the eIF5-CTD, which contains two conserved aromatic/acidic boxes. Six of the point mutations derepressed GCN4 translation independent of eIF2 phosphorylation (Gcd− phenotype) at a permissive temperature, directly implicating eIF5-CTD in the eIF2/GTP/Met-tRNAi Met ternary complex binding process required for GCN4 translational control. In addition, stronger restriction of eIF5-CTD function at an elevated temperature led to failure to derepress GCN4 translation (Gcn− phenotype) in all of the mutants, most likely due to leaky scanning of the first upstream open reading frame of GCN4 mRNA. This latter result directly implicates eIF5-CTD in the process of accurate scanning for, or recognition of, AUG codons. Taken together, our results indicate that eIF5-CTD plays a critical role in both the assembly of the 43S complex and the postassembly process in the 48S complex, likely during the scanning process.

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The DAZL and PABP families: RNA-binding proteins with interrelated roles in translational control in oocytes

Reproduction ◽

10.1530/rep-08-0524 ◽

2009 ◽

Vol 137 (4) ◽

pp. 595-617 ◽

Cited By ~ 70

Author(s):

Matthew Brook ◽

Joel W S Smith ◽

Nicola K Gray

Keyword(s):

Gene Expression ◽

Germ Cells ◽

Translational Control ◽

Translational Regulation ◽

Rna Binding ◽

Rna Binding Proteins ◽

Regulation Of Gene Expression ◽

Mrna Translation ◽

Translation Initiation Factor ◽

Initiation Factor

Gametogenesis is a highly complex process that requires the exquisite temporal, spatial and amplitudinal regulation of gene expression at multiple levels. Translational regulation is important in a wide variety of cell types but may be even more prevalent in germ cells, where periods of transcriptional quiescence necessitate the use of post-transcriptional mechanisms to effect changes in gene expression. Consistent with this, studies in multiple animal models have revealed an essential role for mRNA translation in the establishment and maintenance of reproductive competence. While studies in humans are less advanced, emerging evidence suggests that translational regulation plays a similarly important role in human germ cells and fertility. This review highlights specific mechanisms of translational regulation that play critical roles in oogenesis by activating subsets of mRNAs. These mRNAs are activated in a strictly determined temporal manner via elements located within their 3′UTR, which serve as binding sites fortrans-acting factors. While we concentrate on oogenesis, these regulatory events also play important roles during spermatogenesis. In particular, we focus on the deleted in azoospermia-like (DAZL) family of proteins, recently implicated in the translational control of specific mRNAs in germ cells; their relationship with the general translation initiation factor poly(A)-binding protein (PABP) and the process of cytoplasmic mRNA polyadenylation.

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Causal Association between Periodontitis and Parkinson’s Disease: A Bidirectional Mendelian Randomization Study

Genes ◽

10.3390/genes12050772 ◽

2021 ◽

Vol 12 (5) ◽

pp. 772

Author(s):

João Botelho ◽

Vanessa Machado ◽

José João Mendes ◽

Paulo Mascarenhas

Keyword(s):

Parkinson’S Disease ◽

Parkinson's Disease ◽

Instrumental Variables ◽

Mendelian Randomization ◽

Association Studies ◽

European Ancestry ◽

Genome Wide Association Studies ◽

Nucleotide Polymorphisms ◽

Genetic Liability ◽

Bidirectional Association

The latest evidence revealed a possible association between periodontitis and Parkinson’s disease (PD). We explored the causal relationship of this bidirectional association through two-sample Mendelian randomization (MR) in European ancestry populations. To this end, we used openly accessible data of genome-wide association studies (GWAS) on periodontitis and PD. As instrumental variables for periodontitis, seventeen single-nucleotide polymorphisms (SNPs) from a GWAS of periodontitis (1817 periodontitis cases vs. 2215 controls) and eight non-overlapping SNPs of periodontitis from an additional GWAS for validation purposes. Instrumental variables to explore for the reverse causation included forty-five SNPs from a GWAS of PD (20,184 cases and 397,324 controls). Multiple approaches of MR were carried-out. There was no evidence of genetic liability of periodontitis being associated with a higher risk of PD (B = −0.0003, Standard Error [SE] 0.0003, p = 0.26). The eight independent SNPs (B = −0.0000, SE 0.0001, p = 0.99) validated this outcome. We also found no association of genetically primed PD towards periodontitis (B = −0.0001, SE 0.0001, p = 0.19). These MR study findings do not support a bidirectional causal genetic liability between periodontitis and PD. Further GWAS studies are needed to confirm the consistency of these results.

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Pharmacogenomics of Lithium Response in Bipolar Disorder

Pharmaceuticals ◽

10.3390/ph14040287 ◽

2021 ◽

Vol 14 (4) ◽

pp. 287

Author(s):

Courtney M. Vecera ◽

Gabriel R. Fries ◽

Lokesh R. Shahani ◽

Jair C. Soares ◽

Rodrigo Machado-Vieira

Keyword(s):

Bipolar Disorder ◽

Association Studies ◽

Mood Stabilizer ◽

Genome Wide Association Studies ◽

Nucleotide Polymorphisms ◽

Non Coding Rna ◽

Genome Wide ◽

Lithium Response ◽

Genetic Loading ◽

Long Non Coding Rna

Despite being the most widely studied mood stabilizer, researchers have not confirmed a mechanism for lithium’s therapeutic efficacy in Bipolar Disorder (BD). Pharmacogenomic applications may be clinically useful in the future for identifying lithium-responsive patients and facilitating personalized treatment. Six genome-wide association studies (GWAS) reviewed here present evidence of genetic variations related to lithium responsivity and side effect expression. Variants were found on genes regulating the glutamate system, including GAD-like gene 1 (GADL1) and GRIA2 gene, a mutually-regulated target of lithium. In addition, single nucleotide polymorphisms (SNPs) discovered on SESTD1 may account for lithium’s exceptional ability to permeate cell membranes and mediate autoimmune and renal effects. Studies also corroborated the importance of epigenetics and stress regulation on lithium response, finding variants on long, non-coding RNA genes and associations between response and genetic loading for psychiatric comorbidities. Overall, the precision medicine model of stratifying patients based on phenotype seems to derive genotypic support of a separate clinical subtype of lithium-responsive BD. Results have yet to be expounded upon and should therefore be interpreted with caution.

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Investigation of gene–environment interactions in relation to tic severity

Journal of Neural Transmission ◽

10.1007/s00702-021-02396-y ◽

2021 ◽

Author(s):

Mohamed Abdulkadir ◽

Dongmei Yu ◽

Lisa Osiecki ◽

Robert A. King ◽

Thomas V. Fernandez ◽

...

Keyword(s):

Tourette Syndrome ◽

Association Studies ◽

Autism Spectrum ◽

Environment Interaction ◽

Genome Wide Association Studies ◽

Nucleotide Polymorphisms ◽

Linear Regression Models ◽

Compulsive Disorder ◽

Gene Environment ◽

Tic Severity

AbstractTourette syndrome (TS) is a neuropsychiatric disorder with involvement of genetic and environmental factors. We investigated genetic loci previously implicated in Tourette syndrome and associated disorders in interaction with pre- and perinatal adversity in relation to tic severity using a case-only (N = 518) design. We assessed 98 single-nucleotide polymorphisms (SNPs) selected from (I) top SNPs from genome-wide association studies (GWASs) of TS; (II) top SNPs from GWASs of obsessive–compulsive disorder (OCD), attention-deficit/hyperactivity disorder (ADHD), and autism spectrum disorder (ASD); (III) SNPs previously implicated in candidate-gene studies of TS; (IV) SNPs previously implicated in OCD or ASD; and (V) tagging SNPs in neurotransmitter-related candidate genes. Linear regression models were used to examine the main effects of the SNPs on tic severity, and the interaction effect of these SNPs with a cumulative pre- and perinatal adversity score. Replication was sought for SNPs that met the threshold of significance (after correcting for multiple testing) in a replication sample (N = 678). One SNP (rs7123010), previously implicated in a TS meta-analysis, was significantly related to higher tic severity. We found a gene–environment interaction for rs6539267, another top TS GWAS SNP. These findings were not independently replicated. Our study highlights the future potential of TS GWAS top hits in gene–environment studies.

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Correction of eIF2-dependent defects in brain protein synthesis, synaptic plasticity, and memory in mouse models of Alzheimer’s disease

Science Signaling ◽

10.1126/scisignal.abc5429 ◽

2021 ◽

Vol 14 (668) ◽

pp. eabc5429

Author(s):

Mauricio M. Oliveira ◽

Mychael V. Lourenco ◽

Francesco Longo ◽

Nicole P. Kasica ◽

Wenzhong Yang ◽

...

Keyword(s):

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Protein Synthesis ◽

Synaptic Plasticity ◽

Translation Initiation ◽

Mrna Translation ◽

Translation Initiation Factor ◽

Initiation Factor ◽

Postmortem Brain Tissue ◽

Phosphorylated Eif2α

Neuronal protein synthesis is essential for long-term memory consolidation, and its dysregulation is implicated in various neurodegenerative disorders, including Alzheimer’s disease (AD). Cellular stress triggers the activation of protein kinases that converge on the phosphorylation of eukaryotic translation initiation factor 2α (eIF2α), which attenuates mRNA translation. This translational inhibition is one aspect of the integrated stress response (ISR). We found that postmortem brain tissue from AD patients showed increased phosphorylation of eIF2α and reduced abundance of eIF2B, another key component of the translation initiation complex. Systemic administration of the small-molecule compound ISRIB (which blocks the ISR downstream of phosphorylated eIF2α) rescued protein synthesis in the hippocampus, measures of synaptic plasticity, and performance on memory-associated behavior tests in wild-type mice cotreated with salubrinal (which inhibits translation by inducing eIF2α phosphorylation) and in both β-amyloid-treated and transgenic AD model mice. Thus, attenuating the ISR downstream of phosphorylated eIF2α may restore hippocampal protein synthesis and delay cognitive decline in AD patients.

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