Arabidopsis translation initiation factors
            eIF
            iso4G1/2 link repression of
            mRNA
            cap‐binding complex
            eIF
            iso4F assembly with
            RNA
            ‐binding protein
            SOAR
            1‐mediated
            ABA
            signaling

Most transcription in Trypanosoma brucei is constitutive and polycistronic. Consequently, the parasite relies on post-transcriptional mechanisms, especially affecting translation initiation and mRNA decay, to control gene expression both at steady-state and for adaptation to different environments. The parasite has six isoforms of the cap-binding protein EIF4E as well as five EIF4Gs. EIF4E1 does not bind to any EIF4G, instead being associated with a 4E-binding protein, 4EIP. 4EIP represses translation and reduces the stability of a reporter mRNA when artificially tethered to the 3’-UTR, whether or not EIF4E1 is present. 4EIP is essential during the transition from the mammalian bloodstream form to the procyclic form that lives in the Tsetse vector. In contrast, EIF4E1 is dispensable during differentiation, but is required for establishment of growing procyclic forms. In Leishmania, there is some evidence that EIF4E1 might be active in translation initiation, via direct recruitment of EIF3. However in T. brucei, EIF4E1 showed no detectable association with other translation initiation factors, even in the complete absence of 4EIP. There was some evidence for interactions with NOT complex components, but if these occur they must be weak and transient. We found that EIF4E1is less abundant in the absence of 4EIP, and RNA pull-down results suggested this might occur through co-translational complex assembly. We also report that 4EIP directly recruits the cytosolic terminal uridylyl transferase TUT3 to EIF4E1/4EIP complexes. There was, however, no evidence that TUT3 is essential for 4EIP function.

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Translational Repression by RNA-Binding Protein TIAR

Molecular and Cellular Biology ◽

10.1128/mcb.26.7.2716-2727.2006 ◽

2006 ◽

Vol 26 (7) ◽

pp. 2716-2727 ◽

Cited By ~ 97

Author(s):

Krystyna Mazan-Mamczarz ◽

Ashish Lal ◽

Jennifer L. Martindale ◽

Tomoko Kawai ◽

Myriam Gorospe

Keyword(s):

Rna Binding ◽

Binding Protein ◽

Protein Biosynthesis ◽

Rna Binding Protein ◽

Elongation Factor ◽

Initiation Factor ◽

Translation Elongation ◽

Initiation Factors ◽

Translation Initiation Factors ◽

Cellular Translation

ABSTRACT The RNA-binding protein TIAR has been proposed to inhibit protein synthesis transiently by promoting the formation of translationally silent stress granules. Here, we report the selective binding of TIAR to several mRNAs encoding translation factors such as eukaryotic initiation factor 4A (eIF4A) and eIF4E (translation initiation factors), eEF1B (a translation elongation factor), and c-Myc (which transcriptionally controls the expression of numerous translation regulatory proteins). TIAR bound the 3′-untranslated regions of these mRNAs and potently suppressed their translation, particularly in response to low levels of short-wavelength UV (UVC) irradiation. The UVC-imposed global inhibition of the cellular translation machinery was significantly relieved after silencing of TIAR expression. We propose that the TIAR-mediated inhibition of translation factor expression elicits a sustained repression of protein biosynthesis in cells responding to stress.

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Translational specialization in pluripotency by RBPMS poises future lineage-decisions

10.1101/2021.04.12.439420 ◽

2021 ◽

Author(s):

Deniz Bartsch ◽

Kaustubh Kalamkar ◽

Gaurav Ahuja ◽

Hisham Bazzi ◽

Argyris Papantonis ◽

...

Keyword(s):

Stem Cells ◽

Cell Fate ◽

Translation Initiation ◽

Translational Control ◽

Rna Binding ◽

Rna Binding Protein ◽

Lineage Commitment ◽

Initiation Factors ◽

Translation Initiation Factors ◽

Selective Translation

SUMMARYIn mammals, translation is uniquely regulated at the exit of pluripotency to rapidly reprogram the proteome to enable lineage commitment. Yet, the developmental mediators of translational control and their mode-of-action remain elusive. Using human embryonic stem cells, we identified RBPMS as a vital translation specialization factor that allows selective translation of developmental regulators. RBPMS-driven translational control balances the abundance of cell-fate regulators to enable accurate lineage decisions upon receiving differentiation cues. RBPMS loss, without affecting pluripotency, specifically and severely impedes mesoderm specification and subsequent cardiogenesis. Mechanistically, the direct binding of RBPMS to 3’UTR allows selective translation of transcripts encoding developmental regulators including integral components of central morphogen signaling networks specifying mesoderm. RBPMS-loss results in aberrant retention of key translation initiation factors on ribosomal complexes. Our data unveil how emerging lineage choices from pluripotency are controlled by translational specialization via ribosomal platforms acting as a regulatory nexus for developmental cell fate decisions.IN BRIEFFuture lineage choices from pluripotency are controlled by translational specialization. The RNA binding protein RBPMS is a vital translational specialization factor that unlocks the mesoderm commitment potential of pluripotent stem cells by enabling selective translation of cell-fate regulators instructing lineage decisions.HIGHLIGHTSLineage choices emerging from pluripotency are selectively controlled by translational specializationThe RNA-binding protein RBPMS is a translation specialization factor dedicated to mesoderm commitmentRBPMS-driven translational specialization enables accurate lineage commitment via balancing the availability of key morphogen signaling componentsRBPMS loss selectively impairs mesoderm commitment and subsequently impedes cardiogenesisRBPMS binds the 3’UTRs of target mRNAs to allow their selective translation; its depletion leads to aberrant retention of key translation initiation factors on ribosomal complexes

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Translation Initiation Factors eIF-iso4G and eIF-4B Interact with the Poly(A)-binding Protein and Increase Its RNA Binding Activity

Journal of Biological Chemistry ◽

10.1074/jbc.272.26.16247 ◽

1997 ◽

Vol 272 (26) ◽

pp. 16247-16255 ◽

Cited By ~ 172

Author(s):

Hanh Le ◽

Robert L. Tanguay ◽

M. Luisa Balasta ◽

Chin-Chuan Wei ◽

Karen S. Browning ◽

...

Keyword(s):

Translation Initiation ◽

Rna Binding ◽

Binding Protein ◽

Binding Activity ◽

Initiation Factors ◽

Translation Initiation Factors

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RNA-binding protein FXR1 drives cMYC translation by mRNA circularization through eIF4F recruitment in ovarian cancer

10.1101/2020.07.19.210252 ◽

2020 ◽

Author(s):

Jasmine George ◽

Yongsheng Li ◽

Deepak Parashar ◽

Shirng-Wern Tsaih ◽

Prachi Gupta ◽

...

Keyword(s):

Ovarian Cancer ◽

Translation Initiation ◽

Rna Binding ◽

Rna Binding Protein ◽

Eukaryotic Translation ◽

Initiation Factors ◽

Eif4f Complex ◽

Translation Initiation Factors ◽

Eukaryotic Translation Initiation ◽

Eukaryotic Translation Initiation Factors

AbstractBackgroundThe RNA-binding protein FXR1 (fragile X-related protein 1) has been implicated as an important regulator of post-transcriptional changes of mRNAs. However, its role in mRNA circularization and recruitment of eukaryotic translation initiation factors for protein translation remains obscure. Here, we aimed to investigate the molecular mechanisms and potential clinical applications of FXR1 in ovarian cancer growth and progression.MethodsFXR1 copy number variation, mRNA expression, protein levels, and their association with prognosis were determined in clinical datasets. An orthotopic ovarian cancer model and bioluminescence imaging were used for preclinical evaluation of FXR1 in vivo. Reverse phase protein arrays (RPPA) and qPCR arrays were performed to identify FXR1’s key targets and downstream effects. SUnSET and polysome profiling were used to determine the translational effects of FXR1. Immunoprecipitation and immunofluorescence were performed to identify the interaction between FXR1 and cMYC mRNA and eIF4F complex. RNA-immunoprecipitation (RIP), RNA electrophoretic mobility shift assays (REMSA), proximity ligation assays (PLA), and biochemical assays were used to identify the specific site on cMYC mRNA to which FXR1 binds to promote mRNA circularization and translation.ResultsWe found that amplification and copy-gain of FXR1 increased the expression of FXR1 mRNA and FXR1 protein in ovarian cancer patients, and these events associated with poor prognosis. We demonstrated that FXR1 binds to AU-rich elements (ARE) within the 3’ untranslated region (3’UTR) of cMYC. As a consequence, FXR1 binding to cMYC 3’UTR leads to the circularization of mRNA and facilitated the recruitment of eukaryotic translation initiation factors (eIFs) to translation start site for improving protein synthesis.ConclusionWe found that FXR1 upregulates a known oncogene, cMYC, by binding to AU-rich elements within the 3’UTR, leading to the recruitment of the eIF4F complex for cMYC translation. Our findings uncover a novel mechanism of action of FXR1 in tumorigenesis and provides opportunities to use FXR1 and its downstream effectors as biomarkers or therapeutic targets in ovarian and other cancers.

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Mechanisms of translation repression by the EIF4E1-4EIP cap-binding complex of Trypanosoma brucei: potential roles of the NOT complex and a terminal uridylyl transferase

10.1101/2021.05.19.444837 ◽

2021 ◽

Author(s):

Franziska Falk ◽

Kevin Kamanyi Marucha ◽

Christine Clayton

Keyword(s):

Trypanosoma Brucei ◽

Translation Initiation ◽

Binding Protein ◽

Initiation Factors ◽

Control Gene Expression ◽

Translation Initiation Factors ◽

Cap Binding Complex ◽

Competing Models ◽

The Stability ◽

Reporter Mrna

Most transcription in Trypanosoma brucei is constitutive and polycistronic. Consequently, the parasite relies on post-transcriptional mechanisms, especially affecting translation initiation and mRNA decay, to control gene expression both at steady-state and for adaptation to different environments. The parasite has six isoforms of the cap-binding protein EIF4E as well as five EIF4Gs. EIF4E1 does not bind to any EIF4G, instead being associated with a 4E-binding protein, 4EIP. 4EIP represses translation and reduces the stability of a reporter mRNA when artificially tethered to the 3'-UTR, whether or not EIF4E1 is present. 4EIP is essential during the transition from the mammalian bloodstream form to the procyclic form that lives in the Tsetse vector. In contrast, EIF4E1 is dispensable during differentiation, but is required for establishment of growing procyclic forms. There are two competing models for EIF4E1 function: either EIF4E1 has translation initiation activity that is inhibited by 4EIP, or EIF4E1 acts only as an inhibitor. We here provide evidence for the second hypothesis. Even in the complete absence of 4EIP, EIF4E1 showed no detectable association with other translation initiation factors, and 4EIP loss caused no detectable change in 4E1-associated mRNAs. We found that 4EIP stabilises EIF4E1, probably through co-translational complex assembly, and that 4EIP directly recruits the cytosolic terminal uridylyl transferase TUT3 to EIF4E1/4EIP complexes. There was, however, no evidence that TUT3 is essential for 4EIP function; instead, some evidence implicated the NOT deadenylase complex.

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Insights from a Paradigm Shift: How the Poly(A)-Binding Protein Brings Translating mRNAs Full Circle

New Journal of Science ◽

10.1155/2014/873084 ◽

2014 ◽

Vol 2014 ◽

pp. 1-16 ◽

Cited By ~ 2

Author(s):

Daniel R. Gallie

Keyword(s):

Translation Initiation ◽

Paradigm Shift ◽

Binding Protein ◽

Ribosomal Subunit ◽

Physical Interaction ◽

New Paradigm ◽

Initiation Factors ◽

Full Circle ◽

Translation Initiation Factors ◽

Cap Binding Complex

In recent years, our thinking of how the initiation of protein synthesis occurs has changed dramatically. Initiation was thought to involve only events occurring at or near the 5′-cap structure, which serves as the binding site for the cap-binding complex, a group of translation initiation factors (eIFs) that facilitate the binding of the 40 S ribosomal subunit to an mRNA. Because the poly(A)-binding protein (PABP) binds the poly(A) tail present at the 3′-terminus of an mRNA, it was long thought to play no role in translation initiation. In this review, I present evidence from my laboratory that has contributed to the paradigm shift in how we think of mRNAs during translation. The depiction of mRNAs as straight molecules in which the poly(A) tail is far from events occurring at the 5′-end has now been replaced by the concept of a circular mRNA where the interaction between PABP and the cap-binding complex bridges the termini of an mRNA and promotes translation initiation. The research from my laboratory supports the new paradigm that translation of most mRNAs requires a functional and physical interaction between the termini of an mRNA.

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Faculty Opinions recommendation of The double-stranded RNA binding protein 76:NF45 heterodimer inhibits translation initiation at the rhinovirus type 2 internal ribosome entry site.

Faculty Opinions – Post-Publication Peer Review of the Biomedical Literature ◽

10.3410/f.1033130.375126 ◽

2006 ◽

Author(s):

Lee Gehrke

Keyword(s):

Translation Initiation ◽

Internal Ribosome Entry Site ◽

Rna Binding ◽

Binding Protein ◽

Rna Binding Protein ◽

Entry Site ◽

Internal Ribosome Entry ◽

Double Stranded Rna

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Control of Gene Expression by RNA Binding Protein Action on Alternative Translation Initiation Sites

PLoS Computational Biology ◽

10.1371/journal.pcbi.1005198 ◽

2016 ◽

Vol 12 (12) ◽

pp. e1005198 ◽

Cited By ~ 4

Author(s):

Angela Re ◽

Levi Waldron ◽

Alessandro Quattrone

Keyword(s):

Gene Expression ◽

Translation Initiation ◽

Rna Binding ◽

Binding Protein ◽

Rna Binding Protein ◽

Control Of Gene Expression ◽

Alternative Translation Initiation ◽

Alternative Translation

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Polypyrimidine-tract-binding protein: a multifunctional RNA-binding protein

Biochemical Society Transactions ◽

10.1042/bst0360641 ◽

2008 ◽

Vol 36 (4) ◽

pp. 641-647 ◽

Cited By ~ 191

Author(s):

Kirsty Sawicka ◽

Martin Bushell ◽

Keith A. Spriggs ◽

Anne E. Willis

Keyword(s):

Translation Initiation ◽

Cellular Localization ◽

Rna Binding ◽

Binding Protein ◽

Control Cell ◽

Rna Binding Protein ◽

Alternative Form ◽

Polypyrimidine Tract ◽

Polypyrimidine Tract Binding ◽

Polypyrimidine Tract Binding Protein

PTB (polypyrimidine-tract-binding protein) is a ubiquitous RNA-binding protein. It was originally identified as a protein with a role in splicing but it is now known to function in a large number of diverse cellular processes including polyadenylation, mRNA stability and translation initiation. Specificity of PTB function is achieved by a combination of changes in the cellular localization of this protein (its ability to shuttle from the nucleus to the cytoplasm is tightly controlled) and its interaction with additional proteins. These differences in location and trans-acting factor requirements account for the fact that PTB acts both as a suppressor of splicing and an activator of translation. In the latter case, the role of PTB in translation has been studied extensively and it appears that this protein is required for an alternative form of translation initiation that is mediated by a large RNA structural element termed an IRES (internal ribosome entry site) that allows the synthesis of picornaviral proteins and cellular proteins that function to control cell growth and cell death. In the present review, we discuss how PTB regulates these disparate processes.

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