Coping with stress: eIF2 kinases and translational control

2006 ◽  
Vol 34 (1) ◽  
pp. 7-11 ◽  
Author(s):  
R.C. Wek ◽  
H.-Y. Jiang ◽  
T.G. Anthony
Keyword(s):  
Gene Expression ◽  
Transcription Factors ◽  
Protein Kinases ◽  
Translational Control ◽  
Environmental Stresses ◽  
Initiation Factor ◽  
Nutritional Deficiencies ◽  
Basic Leucine Zipper ◽  
Eif2α Kinase ◽  
Eif2 Phosphorylation

In response to environmental stresses, a family of protein kinases phosphorylate eIF2 (eukaryotic initiation factor 2) to alleviate cellular injury or alternatively induce apoptosis. Phosphorylation of eIF2 reduces global translation, allowing cells to conserve resources and to initiate a reconfiguration of gene expression to effectively manage stress conditions. Accompanying this general protein synthesis control, eIF2 phosphorylation induces translation of specific mRNAs, such as that encoding the bZIP (basic leucine zipper) transcriptional regulator ATF4 (activating transcription factor 4). ATF4 also enhances the expression of additional transcription factors, ATF3 and CHOP (CCAAT/enhancer-binding protein homologous protein)/GADD153 (growth arrest and DNA-damage-inducible protein), that assist in the regulation of genes involved in metabolism, the redox status of the cells and apoptosis. Reduced translation by eIF2 phosphorylation can also lead to activation of stress-related transcription factors, such as NF-κB (nuclear factor κB), by lowering the steady-state levels of short-lived regulatory proteins such as IκB (inhibitor of NF-κB). While many of the genes induced by eIF2 phosphorylation are shared between different environmental stresses, eIF2 kinases function in conjunction with other stress-response pathways, such as those regulated by mitogen-activated protein kinases, to elicit gene expression programmes that are tailored for the specific stress condition. Loss of eIF2 kinase pathways can have important health consequences. Mice devoid of the eIF2 kinase GCN2 [general control non-derepressible-2 or EIF2AK4 (eIF2α kinase 4)] show sensitivity to nutritional deficiencies and aberrant eating behaviours, and deletion of PEK [pancreatic eIF2α kinase or PERK (RNA-dependent protein kinase-like endoplasmic reticulum kinase) or EIF2AK3] leads to neonatal insulin-dependent diabetes, epiphyseal dysplasia and hepatic and renal complications.

scholarly journals Novel Membrane-Bound eIF2α Kinase in the Flagellar Pocket of Trypanosoma brucei

2007 ◽  
Vol 6 (11) ◽  
pp. 1979-1991 ◽  
Author(s):  
Maria Carolina S. Moraes ◽  
Teresa C. L. Jesus ◽  
Nilce N. Hashimoto ◽  
Madhusudan Dey ◽  
Kevin J. Schwartz ◽  
...  
Keyword(s):  
Gene Expression ◽  
Trypanosoma Brucei ◽  
Translational Control ◽  
Catalytic Domain ◽  
Sequence Similarity ◽  
Initiation Factor ◽  
Flagellar Pocket ◽  
Human Pathogens ◽  
Eif2α Kinase

ABSTRACT Translational control mediated by phosphorylation of the alpha subunit of the eukaryotic initiation factor 2 (eIF2α) is central to stress-induced programs of gene expression. Trypanosomatids, important human pathogens, display differentiation processes elicited by contact with the distinct physiological milieu found in their insect vectors and mammalian hosts, likely representing stress situations. Trypanosoma brucei, the agent of African trypanosomiasis, encodes three potential eIF2α kinases (TbeIF2K1 to -K3). We show here that TbeIF2K2 is a transmembrane glycoprotein expressed both in procyclic and in bloodstream forms. The catalytic domain of TbeIF2K2 phosphorylates yeast and mammalian eIF2α at Ser51. It also phosphorylates the highly unusual form of eIF2α found in trypanosomatids specifically at residue Thr169 that corresponds to Ser51 in other eukaryotes. T. brucei eIF2α, however, is not a substrate for GCN2 or PKR in vitro. The putative regulatory domain of TbeIF2K2 does not share any sequence similarity with known eIF2α kinases. In both procyclic and bloodstream forms TbeIF2K2 is mainly localized in the membrane of the flagellar pocket, an organelle that is the exclusive site of exo- and endocytosis in these parasites. It can also be detected in endocytic compartments but not in lysosomes, suggesting that it is recycled between endosomes and the flagellar pocket. TbeIF2K2 location suggests a relevance in sensing protein or nutrient transport in T. brucei, an organism that relies heavily on posttranscriptional regulatory mechanisms to control gene expression in different environmental conditions. This is the first membrane-associated eIF2α kinase described in unicellular eukaryotes.

Upregulation of eIF4E in Nucleophosmin 1 (NPM1) Haploinsufficient Cells Alters CCAAT Enhancer Binding Protein Alpha (C/EBPα) Activity: Implications for MDS and AML

Blood ◽  
2011 ◽  
Vol 118 (21) ◽  
pp. 2432-2432
Author(s):  
Nirmalee Abayasekara ◽  
Michelle Levine ◽  
Niccolo Bolli ◽  
Hong Sun ◽  
Matthew Silver ◽  
...  
Keyword(s):  
Gene Expression ◽  
Translation Initiation ◽  
Translational Control ◽  
Conflicts Of Interest ◽  
Mrna Translation ◽  
Dominant Negative ◽  
Full Length ◽  
Initiation Factor ◽  
Specific Gene ◽  
Specific Gene Expression

Abstract Abstract 2432 NPM1, is a highly conserved, ubiquitous nucleolar phosphoprotein that belongs to the nucleoplasmin family of nuclear chaperones. NPM1−/− mice die at mid-gestation (E11.5) from anemia, underscoring the gene's role in embryonic development. NPM1 is one of the most frequently mutated genes in AML. Mutations in NPM1 are found in 50% of normal karyotype AML patients, and mutant NPM1 (NPMc+) is aberrantly located in the cytoplasm of leukemic blasts in about 35% of all AML patients. Furthermore, NPM1 maps to a region on chromosome 5q that is the target of deletions in both de novo and therapy-associated human MDS. NPM1 thus acts as a haploinsufficient tumor suppressor in the hematological compartment, although the mechanism of its contribution to dysmyelopoiesis remains unknown. NPM-1+/− mice develop a hematological syndrome similar to that observed in human MDS, and develop AML over time. The NPM1 deficient model therefore provides a platform to interrogate the molecular basis of MDS. We identified nucleophosmin (NPM1) in a screen for protein binding partners of C/EBPα. C/EBPα is a single exon gene, but is expressed as two isoforms that arise by alternate translation start sites to yield a full length C/EBPα p42 and a truncated dominant negative C/EBPα p30 isoform. Translational control of isoform expression is orchestrated by a conserved upstream open reading frame (uORF) in the 5' untranslated region (5'UTR) and modulated by the translation initiation factors eIF4E and eIF2. We generated factor-dependent myeloid cell lines from the bone marrow of Npm1+/+ and Npm1+/− mice. These lines are IL-3-dependent and inducible toward neutrophil maturation with GM-CSF and/ or all- trans retinoic acid (ATRA). Neutrophils derived from MNPM1+/− cells display defective neutrophil-specific gene expression, including a cassette of C/EBPα-dependent genes. These observations led us to postulate that myeloid abnormalities in NPM1 deficiency reflect an aberrant NPM1-C/EBPα axis. We show that NPM1 haploinsufficiency upregulates eIF4E (eukaryotic initiation factor 4E) (but not eIF2), which binds the mRNA-Cap (m7-GTP) as part of the mRNA translation initiation complex, eIF4F. Increased eIF4E is observed in about 30% of all malignancies. Initial increased eIF4E levels in MNPM+/− cells likely reflect transcriptional activation by the oncoprotein c-Myc, protein levels of which are also elevated in MNPM1+/− cells. We propose that increased eIF4E then induces increased C/EBPαp30 translation. C/EBPαp30 is a dominant negative inhibitor of full length C/EBPαp42 activity and disrupts normal neutrophil development. Furthermore, we demonstrate that C/EBPαp30 but not C/EBPαp42, activates the eIF4E promoter. We propose a positive feedback loop, wherein increased C/EBPαp30 induced by eIF4E further increases the expression of eIF4E. Our data suggest that NPM1 deficiency modulates neutrophil-specific gene expression by altering C/EBPα. We propose an aberrant feed-forward mechanism that increases levels of both eIF4E and C/EBPαp30 and likely contributes to MDS associated with NPM1 deficiency. Disclosures: No relevant conflicts of interest to declare.

scholarly journals Phosphorylation of Eukaryotic Initiation Factor 2 by Heme-Regulated Inhibitor Kinase-Related Protein Kinases in Schizosaccharomyces pombe Is Important for Resistance to Environmental Stresses

2002 ◽  
Vol 22 (20) ◽  
pp. 7134-7146 ◽  
Author(s):  
Ke Zhan ◽  
Krishna M. Vattem ◽  
Bettina N. Bauer ◽  
Thomas E. Dever ◽  
Jane-Jane Chen ◽  
...  
Keyword(s):  
Protein Synthesis ◽  
Schizosaccharomyces Pombe ◽  
Environmental Stresses ◽  
Initiation Factor ◽  
Eukaryotic Initiation Factor ◽  
Α Subunit ◽  
Eukaryotic Initiation Factor 2 ◽  
Initiation Factor 2 ◽  
Eif2α Kinase

ABSTRACT Protein synthesis is regulated by the phosphorylation of the α subunit of eukaryotic initiation factor 2 (eIF2α) in response to different environmental stresses. One member of the eIF2α kinase family, heme-regulated inhibitor kinase (HRI), is activated under heme-deficient conditions and blocks protein synthesis, principally globin, in mammalian erythroid cells. We identified two HRI-related kinases from Schizosaccharomyces pombe which have full-length homology with mammalian HRI. The two HRI-related kinases, named Hri1p and Hri2p, exhibit autokinase and kinase activity specific for Ser-51 of eIF2α, and both activities were inhibited in vitro by hemin, as previously described for mammalian HRI. Overexpression of Hri1p, Hri2p, or the human eIF2α kinase, double-stranded-RNA-dependent protein kinase (PKR), impeded growth of S. pombe due to elevated phosphorylation of eIF2α. Cells from strains with deletions of the hri1+ and hri2+ genes, individually or in combination, exhibited a reduced growth rate when exposed to heat shock or to arsenic compounds. Measurements of in vivo phosphorylation of eIF2α suggest that Hri1p and Hri2p differentially phosphorylate eIF2α in response to these stress conditions. These results demonstrate that HRI-related enzymes are not unique to vertebrates and suggest that these eIF2α kinases are important participants in diverse stress response pathways in some lower eukaryotes.

scholarly journals Selective Translation Complex Profiling Reveals Staged Initiation and Co-translational Assembly of Initiation Factor Complexes

2019 ◽  
Author(s):  
Susan Wagner ◽  
Anna Herrmannová ◽  
Vladislava Hronová ◽  
Neelam Sen ◽  
Ross D. Hannan ◽  
...  
Keyword(s):  
Gene Expression ◽  
Translational Control ◽  
Mammalian Cells ◽  
Regulation Of Gene Expression ◽  
Ribosome Profiling ◽  
Initiation Factor ◽  
Start Codon ◽  
Codon Recognition ◽  
Initiation Phase ◽  
Gene Expression Studies

SUMMARYTranslational control targeting mainly the initiation phase is central to the regulation of gene expression. Understanding all of its aspects requires substantial technological advancements. Here we modified yeast Translational Complex Profile sequencing (TCP-seq), related to ribosome profiling, and adopted it for mammalian cells. Human TCP-seq, capable of capturing footprints of 40S subunits (40Ses) in addition to 80S ribosomes (80Ses), revealed that mammalian and yeast 40Ses distribute similarly across 5’UTRs indicating considerable evolutionary conservation. We further developed a variation called Selective TCP-seq (Sel-TCP-seq) enabling selection for 40Ses and 80Ses associated with an immuno-targeted factor in yeast and human. Sel-TCP-seq demonstrated that eIF2 and eIF3 travel along 5’UTRs with scanning 40Ses to successively dissociate upon start codon recognition. Manifesting the Sel-TCP-seq versatility for gene expression studies, we also identified four initiating 48S conformational intermediates, provided novel insights into ATF4 and GCN4 mRNA translational control, and demonstrated co-translational assembly of initiation factor complexes.

scholarly journals Cellular Phosphorylation Signaling and Gene Expression in Drought Stress Responses: ABA-Dependent and ABA-Independent Regulatory Systems

Plants ◽  
2021 ◽  
Vol 10 (4) ◽  
pp. 756
Author(s):  
Fumiyuki Soma ◽  
Fuminori Takahashi ◽  
Kazuko Yamaguchi-Shinozaki ◽  
Kazuo Shinozaki
Keyword(s):  
Gene Expression ◽  
Transcription Factors ◽  
Drought Stress ◽  
Plant Growth ◽  
Protein Kinases ◽  
Stress Responses ◽  
Regulatory Pathways ◽  
Cis Acting ◽  
Regulatory Systems ◽  
Responsive Element

Drought is a severe and complex abiotic stress that negatively affects plant growth and crop yields. Numerous genes with various functions are induced in response to drought stress to acquire drought stress tolerance. The phytohormone abscisic acid (ABA) accumulates mainly in the leaves in response to drought stress and then activates subclass III SNF1-related protein kinases 2 (SnRK2s), which are key phosphoregulators of ABA signaling. ABA mediates a wide variety of gene expression processes through stress-responsive transcription factors, including ABA-RESPONSIVE ELEMENT BINDING PROTEINS (AREBs)/ABRE-BINDING FACTORS (ABFs) and several other transcription factors. Seed plants have another type of SnRK2s, ABA-unresponsive subclass I SnRK2s, that mediates the stability of gene expression through the mRNA decay pathway and plant growth under drought stress in an ABA-independent manner. Recent research has elucidated the upstream regulators of SnRK2s, RAF-like protein kinases, involved in early responses to drought stress. ABA-independent transcriptional regulatory systems and ABA-responsive regulation function in drought-responsive gene expression. DEHYDRATION RESPONSIVE ELEMENT (DRE) is an important cis-acting element in ABA-independent transcription, whereas ABA-RESPONSIVE ELEMENT (ABRE) cis-acting element functions in ABA-responsive transcription. In this review article, we summarize recent advances in research on cellular and molecular drought stress responses and focus on phosphorylation signaling and transcription networks in Arabidopsis and crops. We also highlight gene networks of transcriptional regulation through two major regulatory pathways, ABA-dependent and ABA-independent pathways, that ABA-responsive subclass III SnRK2s and ABA-unresponsive subclass I SnRK2s mediate, respectively. We also discuss crosstalk in these regulatory systems under drought stress.

Novel Mechanisms of Translational Control Linking Inflammation and Thrombosis.

Blood ◽  
2008 ◽  
Vol 112 (11) ◽  
pp. sci-45-sci-45
Author(s):  
Andrew Weyrich ◽  
Hansjörg Schwertz
Keyword(s):  
Gene Expression ◽  
Translational Control ◽  
Mammalian Target Of Rapamycin ◽  
B Cell Lymphoma ◽  
Plasminogen Activator Inhibitor ◽  
Therapeutic Interventions ◽  
Initiation Factor ◽  
Control Synthesis ◽  
Plasminogen Activator Inhibitor 1 ◽  
Expression Pathways

Abstract The anatomy of platelets is unique and deceptively simple with a key feature being that platelets circulate without a nucleus. This has led to a common misconception that platelets lack the machinery to produce new proteins. However, over 40 studies from 1966 to 1997 collectively demonstrated and/or inferred that platelets synthesize protein. Recent investigations have not only confirmed these earlier reports but show that platelets possess a sophisticated translational apparatus consisting of template mRNAs, ribosomes, and translation initiation factors, such as eukaryotic initiation factor(eIF)-4E and eIF-2a. Current estimates indicate that platelets retain 4,000–6,000 transcripts and platelet-derived mRNAs are capped and polyadenylated at the 5′ - and 3′-untranslated regions, respectively. Data from our group also demonstrates that platelets contain a pool of precursor mRNAs (premRNAs), uridine-rich small nuclear RNAs, and essential splicing machinery. In response to activation, platelets splice specific pre-mRNAs into mature mRNAs. Published results from our group and others demonstrate that platelets use their splicing and translational machinery to synthesize new proteins. B-cell lymphoma 3 (Bcl-3), cyclooxygenase-1 (COX-1), integrin αIIbβ3, interleukin-1β (IL-1β), Na+-dependent transporter SVCT2, plasminogen activator inhibitor-1 (PAI-1), and tissue factor (TF) are among the most recently characterized proteins reported to be synthesized by platelets. The synthesis of these proteins is highly regulated and involves numerous checkpoints of control. Synthesis of Bcl-3, for example, is controlled by the mammalian Target of Rapamycin (mTOR), one of the most abundantly expressed proteins in platelets. In contrast, platelets use premRNA splicing pathways to regulate the production of pro-IL-1β protein. Processing of pro-IL-1β into its mature form is dependent on an innate cytosolic molecular complex referred to as the inflammasome. The inflammasome has been described in nucleated cells and consists of nucleotide-binding oligomerization domain (NOD)-like receptors, such as NALP-3, as well as caspase-1. Although not previously-described, recent studies from our group demonstrate that platelets possess a functional inflammasome that regulates pro- IL-1β maturation. Identifying and characterizing gene expression pathways in platelets will be an exciting area of investigation throughout the next decade. Our group is actively searching for new targets and, in addition to the inflammasome, we found that platelets harbor reverse transcriptase (RT) activity. Inhibition of RT activity modulates protein synthesis and differentiation responses in platelets. Gene expression pathways including the inflammasome and RT provide platelets with previously-unrecognized mechanisms for controlling thrombosis and inflammation and may be targets for future therapeutic interventions.

scholarly journals A GCN2-Like Eukaryotic Initiation Factor 2 Kinase Increases the Viability of Extracellular Toxoplasma gondii Parasites

2011 ◽  
Vol 10 (11) ◽  
pp. 1403-1412 ◽  
Author(s):  
Christian Konrad ◽  
Ronald C. Wek ◽  
William J. Sullivan
Keyword(s):  
Toxoplasma Gondii ◽  
Host Cell ◽  
Translational Control ◽  
Translation Initiation Factor ◽  
Initiation Factor ◽  
Eukaryotic Initiation Factor ◽  
New Host ◽  
Content Type ◽  
Initiation Factor 2 ◽  
Eif2α Kinase

ABSTRACT Toxoplasmosis is a significant opportunistic infection caused by the protozoan parasite Toxoplasma gondii , an obligate intracellular pathogen that relies on host cell nutrients for parasite proliferation. Toxoplasma parasites divide until they rupture the host cell, at which point the extracellular parasites must survive until they find a new host cell. Recent studies have indicated that phosphorylation of Toxoplasma eukaryotic translation initiation factor 2-alpha (TgIF2α) plays a key role in promoting parasite viability during times of extracellular stress. Here we report the cloning and characterization of a TgIF2α kinase designated TgIF2K-D that is related to GCN2, a eukaryotic initiation factor 2α (eIF2α) kinase known to respond to nutrient starvation in other organisms. TgIF2K-D is present in the cytosol of both intra- and extracellular Toxoplasma parasites and facilitates translational control through TgIF2α phosphorylation in extracellular parasites. We generated a TgIF2K-D knockout parasite and demonstrated that loss of this eIF2α kinase leads to a significant fitness defect that stems from an inability of the parasite to adequately adapt to the environment outside host cells. This phenotype is consistent with that reported for our nonphosphorylatable TgIF2α mutant (S71A substitution), establishing that TgIF2K-D is the primary eIF2α kinase responsible for promoting extracellular viability of Toxoplasma . These studies suggest that eIF2α phosphorylation and translational control are an important mechanism by which vulnerable extracellular parasites protect themselves while searching for a new host cell. Additionally, TgIF2α is phosphorylated when intracellular parasites are deprived of nutrients, but this can occur independently of TgIF2K-D, indicating that this activity can be mediated by a different TgIF2K.

scholarly journals Pilocytic astrocytoma demethylation and transcriptional landscapes link bZIP transcription factors to immune response

2020 ◽  
Vol 22 (9) ◽  
pp. 1327-1338
Author(s):  
Christian F Aichmüller ◽  
Murat Iskar ◽  
David T W Jones ◽  
Andrey Korshunov ◽  
Bernhard Radlwimmer ◽  
...  
Keyword(s):  
Gene Expression ◽  
Transcription Factors ◽  
Pilocytic Astrocytoma ◽  
Immune Cell ◽  
Sequence Data ◽  
Basic Leucine Zipper ◽  
Deconvolution Analysis ◽  
Immune Infiltration ◽  
Bzip Transcription Factors ◽  
Control Samples

Abstract Background Pilocytic astrocytoma (PA) is the most common pediatric brain tumor. While genome and transcriptome landscapes are well studied, data of the complete methylome, tumor cell composition, and immune infiltration are scarce. Methods We generated whole genome bisulfite sequence (WGBS) data of 9 PAs and 16 control samples and integrated available 154 PA and 57 control methylation array data. RNA sequence data of 49 PAs and 11 control samples as well as gene expression arrays of 248 PAs and 28 controls were used to assess transcriptional activity. Results DNA-methylation patterns of partially methylated domains suggested high stability of the methylomes during tumorigenesis. Comparing tumor and control tissues of infra- and supratentorial location using methylation arrays revealed a site specific pattern. Analysis of WGBS data revealed 9381 significantly differentially methylated regions (DMRs) in PA versus control tissue. Enhancers and transcription factor (TF) motifs of five distinct TF families were found to be enriched in DMRs. Methylation together with gene expression data–based in silico tissue deconvolution analysis indicated a striking variation in the immune cell infiltration in PA. A TF network analysis showed a regulatory relation between basic leucine zipper (bZIP) transcription factors and genes involved in immune-related processes. Conclusion We provide evidence for a link of focal methylation differences and differential gene expression to immune infiltration.

scholarly journals Regulation of eIF4E Guides a Unique Translational Program to Steer Erythroid Maturation

Blood ◽  
2019 ◽  
Vol 134 (Supplement_1) ◽  
pp. 156-156
Author(s):  
Craig M Forester ◽  
Gun Woo-Byeon ◽  
Juan Oses-Prieto ◽  
Al Burlingame ◽  
Maria Barna ◽  
...  
Keyword(s):  
Gene Expression ◽  
Translational Control ◽  
Conflicts Of Interest ◽  
Regulation Of Gene Expression ◽  
Erythroid Differentiation ◽  
Initiation Factor ◽  
Specific Gene ◽  
Erythroid Precursors ◽  
Erythroid Maturation

Erythropoiesis is an intricately orchestrated process responsible for rapidly responding to an array of signaling cues to direct cell fates. While gene expression during erythropoiesis has mainly been studied at the transcription level, regulation of gene expression at the level of translation is still poorly understood. As translational control is one of the fastest steps to regulate protein abundance in the cell, we hypothesize that this mechanism plays an important role to rapidly control protein levels in response to extracellular cues during erythroid differentiation. However, outstanding questions remain on how translational control regulates specific gene programs in early erythroid states including 1.) how mRNA are selected for translation in normal erythropoiesis and 2.) how components of the translational machinery are regulated by upstream signaling pathways to orchestrate the translational landscape. In addressing these questions, we have nuncovered a dynamic interplay between Eukaryotic Initiation Factor 4E (eIF4E), the major mRNA cap binding protein that controls translation initiation and its repressor protein, 4EBP1 in erythropoiesis. Specifically, using in vivo phospho-flow cytometry analysis of the eIF4E-4EBP1 axis, eIF4E activity is high in early erythroid phases and is repressed by 4EBP1 in order to allow erythroid maturation. Surprisingly, high eIF4E activity in early erythroid precursors occurs without an increase in global protein synthesis. Utilizing a model of CD34+ human cord blood cells (HUDEP-2), we show that constitutive overexpression of eIF4E impaired erythropoietic maturation. To capture the specific proteins potentially regulated by eIF4E activity during erythropoiesis, we performed quantitative TMT mass spectrometry during HUDEP-2 erythroid differentiation. Our results revealed that eIF4E controls a specific key network of genes necessary for maintenance of early erythroid precursors. By analyzing the 5' untranslated region (5'UTR) of the eIF4E-dependent mRNA network, we identify a highly conserved, CT-rich motif which is required for these mRNAs to be more efficiently translated with increasing eIF4E levels. These results demonstrate wide-spread translational control of CT-rich mRNAs by eIF4E during early erythropoiesis. We are currently employing DMS-MaPseq to understand whether these motifs are also part of structured RNA elements that confer sensitivity to eIF4E levels. We have further extended these findings to a novel transgenic mouse model we have developed that allows in vivo assessment of increased eIF4E temporally at concise phases of erythroid maturation. Understanding this balance of eIF4E activity provides a novel insight into how of translational control dictates gene expression to determine phases of maturation in a crucial differentiation process. Disclosures No relevant conflicts of interest to declare.

scholarly journals Brd4 modulates the innate immune response through Mnk2–eIF4E pathway-dependent translational control of IκBα

2017 ◽  
Vol 114 (20) ◽  
pp. E3993-E4001 ◽  
Author(s):  
Yan Bao ◽  
Xuewei Wu ◽  
Jinjing Chen ◽  
Xiangming Hu ◽  
Fuxing Zeng ◽  
...  
Keyword(s):  
Gene Expression ◽  
Inflammatory Response ◽  
Translational Control ◽  
Translation Initiation Factor ◽  
Initiation Factor ◽  
Small Subset ◽  
Inflammatory Gene Expression ◽  
Inflammatory Genes ◽  
Inflammatory Gene

Bromodomain-containing factor Brd4 has emerged as an important transcriptional regulator of NF-κB–dependent inflammatory gene expression. However, the in vivo physiological function of Brd4 in the inflammatory response remains poorly defined. We now demonstrate that mice deficient for Brd4 in myeloid-lineage cells are resistant to LPS-induced sepsis but are more susceptible to bacterial infection. Gene-expression microarray analysis of bone marrow-derived macrophages (BMDMs) reveals that deletion of Brd4 decreases the expression of a significant amount of LPS-induced inflammatory genes while reversing the expression of a small subset of LPS-suppressed genes, including MAP kinase-interacting serine/threonine-protein kinase 2 (Mknk2). Brd4-deficient BMDMs display enhanced Mnk2 expression and the corresponding eukaryotic translation initiation factor 4E (eIF4E) activation after LPS stimulation, leading to an increased translation of IκBα mRNA in polysomes. The enhanced newly synthesized IκBα reduced the binding of NF-κB to the promoters of inflammatory genes, resulting in reduced inflammatory gene expression and cytokine production. By modulating the translation of IκBα via the Mnk2–eIF4E pathway, Brd4 provides an additional layer of control for NF-κB–dependent inflammatory gene expression and inflammatory response.

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