scholarly journals The endogenous mex-3 3´UTR is required for germline repression and contributes to optimal fecundity in C. elegans

PLoS Genetics ◽  
2021 ◽  
Vol 17 (8) ◽  
pp. e1009775
Author(s):  
Mennatallah M. Y. Albarqi ◽  
Sean P. Ryder
Keyword(s):  
Cell Fate ◽  
Expression Pattern ◽  
Rna Binding ◽  
Rna Binding Proteins ◽  
Control Cell ◽  
Translation Initiation Factor ◽  
Initiation Factor ◽  
Messenger Rnas ◽  
Allelic Series ◽  
Embryo Viability

RNA regulation is essential to successful reproduction. Messenger RNAs delivered from parent to progeny govern early embryonic development. RNA-binding proteins (RBPs) are the key effectors of this process, regulating the translation and stability of parental transcripts to control cell fate specification events prior to zygotic gene activation. The KH-domain RBP MEX-3 is conserved from nematode to human. It was first discovered in Caenorhabditis elegans, where it is essential for anterior cell fate and embryo viability. Here, we show that loss of the endogenous mex-3 3´UTR disrupts its germline expression pattern. An allelic series of 3´UTR deletion variants identify repressing regions of the UTR and demonstrate that repression is not precisely coupled to reproductive success. We also show that several RBPs regulate mex-3 mRNA through its 3´UTR to define its unique germline spatiotemporal expression pattern. Additionally, we find that both poly(A) tail length control and the translation initiation factor IFE-3 contribute to its expression pattern. Together, our results establish the importance of the mex-3 3´UTR to reproductive health and its expression in the germline. Our results suggest that additional mechanisms control MEX-3 function when 3´UTR regulation is compromised.

scholarly journals Multiple RNA regulatory pathways coordinate the activity and expression pattern of a conserved germline RNA-binding protein

2021 ◽  
Author(s):  
Mennatallah M.Y. Albarqi ◽  
Sean P. Ryder
Keyword(s):  
Cell Fate ◽  
Expression Pattern ◽  
Rna Binding ◽  
Rna Binding Proteins ◽  
Control Cell ◽  
Messenger Rnas ◽  
Allelic Series ◽  
Embryo Viability ◽  
Rna Regulation ◽  
Regulatory Pathways

AbstractRNA regulation is essential to successful reproduction. Messenger RNAs delivered from parent to progeny govern early embryonic development. RNA-binding proteins (RBPs) are the key effectors of this process, controlling the translation and stability of parental transcripts to control cell fate specification events prior to zygotic gene activation. The KH-domain RBP MEX-3 is conserved from nematode to human. It was first discovered in Caenorhabditis elegans, where it is essential for anterior cell fate and embryo viability. Here, we show that mex-3 mRNA is itself regulated by several RBPs to define its unique germline spatiotemporal expression pattern. We also show that both poly(A) tail length control and translational regulation contribute to this expression pattern. Though the 3’UTR is sufficient to establish the germline expression pattern, we show that it is not essential for reproduction. An allelic series of 3’UTR deletion variants identifies repressing regions of the UTR and show that the expression pattern is not precisely coupled to reproductive health. Together, our results define the pathways that govern the spatiotemporal regulation of this highly conserved germline RBP and suggest that redundant mechanisms control MEX-3 function when RNA regulation is compromised.

scholarly journals CAR-1 and Trailer hitch: driving mRNP granule function at the ER?

2006 ◽  
Vol 173 (2) ◽  
pp. 159-163 ◽  
Author(s):  
Carolyn J. Decker ◽  
Roy Parker
Keyword(s):  
Endoplasmic Reticulum ◽  
Cell Fate ◽  
Translational Control ◽  
Translational Regulation ◽  
Rna Binding ◽  
Rna Binding Proteins ◽  
Spindle Pole ◽  
Axis Formation ◽  
Cell Fate Determination ◽  
Messenger Rnas

The targeting of messenger RNAs (mRNAs) to specific subcellular sites for local translation plays an important role in diverse cellular and developmental processes in eukaryotes, including axis formation, cell fate determination, spindle pole regulation, cell motility, and neuronal synaptic plasticity. Recently, a new conserved class of Lsm proteins, the Scd6 family, has been implicated in controlling mRNA function. Depletion or mutation of members of the Scd6 family, Caenorhabditis elegans CAR-1 and Drosophila melanogaster trailer hitch, lead to a variety of developmental phenotypes, which in some cases can be linked to alterations in the endoplasmic reticulum (ER). Scd6/Lsm proteins are RNA binding proteins and are found in RNP complexes associated with translational control of mRNAs, and these complexes can colocalize with the ER. These findings raise the possibility that localization and translational regulation of mRNAs at the ER plays a role in controlling the organization of this organelle.

scholarly journals Translational regulation of Chk1 expression by eIF3a via interaction with the RNA-binding protein HuR

2020 ◽  
Vol 477 (10) ◽  
pp. 1939-1950 ◽  
Author(s):  
Zizheng Dong ◽  
Jianguo Liu ◽  
Jian-Ting Zhang
Keyword(s):  
Translational Regulation ◽  
Rna Binding ◽  
Rna Binding Proteins ◽  
Mrna Translation ◽  
Translation Initiation Factor ◽  
Initiation Factor ◽  
Regulatory Function ◽  
Rna Recognition Motif ◽  
Eukaryotic Translation ◽  
Eukaryotic Translation Initiation

eIF3a is a putative subunit of the eukaryotic translation initiation factor 3 complex. Accumulating evidence suggests that eIF3a may have a translational regulatory function by suppressing translation of a subset of mRNAs while accelerating that of other mRNAs. Albeit the suppression of mRNA translation may derive from eIF3a binding to the 5′-UTRs of target mRNAs, how eIF3a may accelerate mRNA translation remains unknown. In this study, we show that eIF3a up-regulates translation of Chk1 but not Chk2 mRNA by interacting with HuR, which binds directly to the 3′-UTR of Chk1 mRNA. The interaction between eIF3a and HuR occurs at the 10-amino-acid repeat domain of eIF3a and the RNA recognition motif domain of HuR. This interaction may effectively circularize Chk1 mRNA to form an end-to-end complex that has recently been suggested to accelerate mRNA translation. Together with previous findings, we conclude that eIF3a may regulate mRNA translation by directly binding to the 5′-UTR to suppress or by interacting with RNA-binding proteins at 3′-UTRs to accelerate mRNA translation.

scholarly journals RNA-Binding Proteins in Acute Leukemias

2020 ◽  
Vol 21 (10) ◽  
pp. 3409 ◽  
Author(s):  
Konstantin Schuschel ◽  
Matthias Helwig ◽  
Stefan Hüttelmaier ◽  
Dirk Heckl ◽  
Jan-Henning Klusmann ◽  
...  
Keyword(s):  
Cell Fate ◽  
Transcriptional Control ◽  
Binding Proteins ◽  
Rna Binding ◽  
Rna Binding Proteins ◽  
Genetic Diseases ◽  
Clinical Aspects ◽  
Translational Efficiency ◽  
Messenger Rnas ◽  
Acute Leukemias

Acute leukemias are genetic diseases caused by translocations or mutations, which dysregulate hematopoiesis towards malignant transformation. However, the molecular mode of action is highly versatile and ranges from direct transcriptional to post-transcriptional control, which includes RNA-binding proteins (RBPs) as crucial regulators of cell fate. RBPs coordinate RNA dynamics, including subcellular localization, translational efficiency and metabolism, by binding to their target messenger RNAs (mRNAs), thereby controlling the expression of the encoded proteins. In view of the growing interest in these regulators, this review summarizes recent research regarding the most influential RBPs relevant in acute leukemias in particular. The reported RBPs, either dysregulated or as components of fusion proteins, are described with respect to their functional domains, the pathways they affect, and clinical aspects associated with their dysregulation or altered functions.

scholarly journals Regulation of gene expression in trypanosomatids: living with polycistronic transcription

Open Biology ◽  
2019 ◽  
Vol 9 (6) ◽  
pp. 190072 ◽  
Author(s):  
Christine Clayton
Keyword(s):  
Rna Polymerase Ii ◽  
Binding Proteins ◽  
Rna Binding ◽  
Rna Binding Proteins ◽  
Regulation Of Gene Expression ◽  
Translation Initiation Factor ◽  
Initiation Factor ◽  
Transcription Control ◽  
Individual Gene ◽  
Polycistronic Transcription

In trypanosomes, RNA polymerase II transcription is polycistronic and individual mRNAs are excised by trans -splicing and polyadenylation. The lack of individual gene transcription control is compensated by control of mRNA processing, translation and degradation. Although the basic mechanisms of mRNA decay and translation are evolutionarily conserved, there are also unique aspects, such as the existence of six cap-binding translation initiation factor homologues, a novel decapping enzyme and an mRNA stabilizing complex that is recruited by RNA-binding proteins. High-throughput analyses have identified nearly a hundred regulatory mRNA-binding proteins, making trypanosomes valuable as a model system to investigate post-transcriptional regulation.

eIF4E-binding proteins: new factors, new locations, new roles

2014 ◽  
Vol 42 (4) ◽  
pp. 1238-1245 ◽  
Author(s):  
Anastasiia Kamenska ◽  
Clare Simpson ◽  
Nancy Standart
Keyword(s):  
Binding Proteins ◽  
Rna Binding ◽  
Gene Expression Regulation ◽  
Rna Binding Proteins ◽  
Ribosomal Subunit ◽  
Translation Initiation Factor ◽  
Initiation Factor ◽  
Eukaryotic Initiation Factor 4E ◽  
New Locations ◽  
Specific Mrnas

The cap-binding translation initiation factor eIF4E (eukaryotic initiation factor 4E) is central to protein synthesis in eukaryotes. As an integral component of eIF4F, a complex also containing the large bridging factor eIF4G and eIF4A RNA helicase, eIF4E enables the recruitment of the small ribosomal subunit to the 5′ end of mRNAs. The interaction between eIF4E and eIF4G via a YXXXXLϕ motif is regulated by small eIF4E-binding proteins, 4E-BPs, which use the same sequence to competitively bind eIF4E thereby inhibiting cap-dependent translation. Additional eIF4E-binding proteins have been identified in the last 10–15 years, characterized by the YXXXXLϕ motif, and by interactions (many of which remain to be detailed) with RNA-binding proteins, or other factors in complexes that recognize the specific mRNAs. In the present article, we focus on the metazoan 4E-T (4E-transporter)/Cup family of eIF4E-binding proteins, and also discuss very recent examples in yeast, fruitflies and humans, some of which predictably inhibit translation, while others may result in mRNA decay or even enhance translation; altogether considerably expanding our understanding of the roles of eIF4E-binding proteins in gene expression regulation.

scholarly journals PTBP1 mRNA isoforms and regulation of their translation

2018 ◽  
Author(s):  
Luisa M Arake de Tacca ◽  
Mia C Pulos ◽  
Stephen N Floor ◽  
Jamie Cate
Keyword(s):  
Cell Cycle ◽  
Alternative Splicing ◽  
Binding Proteins ◽  
Rna Binding ◽  
Rna Binding Proteins ◽  
Translation Initiation Factor ◽  
Protein Isoforms ◽  
Initiation Factor ◽  
Dependent Manner ◽  
Mrna Isoforms

Polypyrimidine tract-binding proteins (PTBPs) are RNA binding proteins that regulate a number of post-transcriptional events. Human PTBP1 transits between the nucleus and cytoplasm and is thought to regulate RNA processes in both. However, information about PTBP1 mRNA isoforms and regulation of PTPB1 expression remain incomplete. Here we mapped the major PTBP1 mRNA isoforms in HEK293T cells, and identified alternative 5' and 3' untranslated regions (5' UTRs, 3' UTRs) as well as alternative splicing patterns in the protein coding region. We also assessed how the observed PTBP1 mRNA isoforms contribute to PTBP1 expression in different phases of the cell cycle. Previously, PTBP1 mRNAs were shown to crosslink to eukaryotic translation initiation factor 3 (eIF3). We find that eIF3 binds differently to each PTBP1 mRNA isoform in a cell cycle-dependent manner. We also observe a strong correlation between eIF3 binding to PTBP1 mRNAs and repression of PTBP1 levels during the S phase of the cell cycle. Our results provide evidence of translational regulation of PTBP1 protein levels during the cell cycle, which may affect downstream regulation of alternative splicing and translation mediated by PTBP1 protein isoforms.

scholarly journals Post-Transcriptional Regulation of Alpha One Antitrypsin by a Proteasome Inhibitor

2020 ◽  
Vol 21 (12) ◽  
pp. 4318
Author(s):  
Lang Rao ◽  
Yi Xu ◽  
Lucas Charles Reineke ◽  
Abhisek Bhattacharya ◽  
Alexey Tyryshkin ◽  
...  
Keyword(s):  
Proteasome Inhibitor ◽  
Rna Binding ◽  
Rna Binding Proteins ◽  
Proteasome Inhibitors ◽  
Serine Proteinase ◽  
Induced Pluripotent Stem Cell ◽  
Translation Initiation Factor ◽  
Cellular Damage ◽  
Initiation Factor ◽  
Pulmonary Tissue

Alpha one antitrypsin (α1AT), a serine proteinase inhibitor primarily produced by the liver, protects pulmonary tissue from neutrophil elastase digestion. Mutations of the SERPINA1 gene results in a misfolded α1AT protein which aggregates inside hepatocytes causing cellular damage. Therefore, inhibition of mutant α1AT production is one practical strategy to alleviate liver damage. Here we show that proteasome inhibitors can selectively downregulate α1AT expression in human hepatocytes by suppressing the translation of α1AT. Translational suppression of α1AT is mediated by phosphorylation of eukaryotic translation initiation factor 2α and increased association of RNA binding proteins, especially stress granule protein Ras GAP SH3 binding protein (G3BP1), with α1AT mRNA. Treatment of human-induced pluripotent stem cell-derived hepatocytes with a proteasome inhibitor also results in translational inhibition of mutant α1AT in a similar manner. Together we revealed a previously undocumented role of proteasome inhibitors in the regulation of α1AT translation.

scholarly journals DAP5 enables translation re-initiation on structured messenger RNAs

2021 ◽  
Author(s):  
Ramona Weber ◽  
Leon Kleemann ◽  
Insa Hirschberg ◽  
Min-Yi Chung ◽  
Eugene Valkov ◽  
...  
Keyword(s):  
Cell Fate ◽  
Molecular Mechanisms ◽  
Mutational Analysis ◽  
Ribosome Profiling ◽  
Open Reading Frames ◽  
Translation Initiation Factor ◽  
Initiation Factor ◽  
Messenger Rnas ◽  
Upstream Open Reading Frames ◽  
Reading Frames

SummaryHalf of mammalian transcripts contain short upstream open reading frames (uORFs) that potentially regulate translation of the downstream coding sequence (CDS). The molecular mechanisms governing these events remain poorly understood. Here we find that the non-canonical initiation factor Death-associated protein 5 (DAP5 or eIF4G2) is selectively required for re-initiation at the main CDS following uORF translation. Using ribosome profiling and luciferase-based reporters coupled with mutational analysis we show that DAP5-mediated re-initiation occurs on messenger RNAs (mRNAs) with long, structure-prone 5′ leader sequences and persistent uORF translation. These mRNAs preferentially code for signalling factors such as kinases and phosphatases. We also report that cap/eIF4F- and eIF4A-dependent recruitment of DAP5 to the mRNA facilitates re-initiation by unrecycled post-termination 40S subunits. Our study reveals important mechanistic insights into how a non-canonical translation initiation factor involved in stem cell fate shapes the synthesis of specific signalling factors.

scholarly journals Hiding in Plain Sight: Formation and Function of Stress Granules During Microbial Infection of Mammalian Cells

2021 ◽  
Vol 8 ◽  
Author(s):  
Alistair Tweedie ◽  
Tracy Nissan
Keyword(s):  
Translation Initiation ◽  
Mammalian Cells ◽  
Rna Binding ◽  
Rna Binding Proteins ◽  
Large Body ◽  
Translation Initiation Factor ◽  
Initiation Factor ◽  
Microbial Infection ◽  
Host Cell Response ◽  
Microbial Infections

Stress granule (SG) formation is a host cell response to stress-induced translational repression. SGs assemble with RNA-binding proteins and translationally silent mRNA. SGs have been demonstrated to be both inhibitory to viruses, as well as being subverted for viral roles. In contrast, the function of SGs during non-viral microbial infections remains largely unexplored. A handful of microbial infections have been shown to result in host SG assembly. Nevertheless, a large body of evidence suggests SG formation in hosts is a widespread response to microbial infection. Diverse stresses caused by microbes and their products can activate the integrated stress response in order to inhibit translation initiation through phosphorylation of the eukaryotic translation initiation factor 2α (eIF2α). This translational response in other contexts results in SG assembly, suggesting that SG assembly can be a general phenomenon during microbial infection. This review explores evidence for host SG formation in response to bacterial, fungal, and protozoan infection and potential functions of SGs in the host and for adaptations of the pathogen.

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