scholarly journals Near-Cognate Codons Contribute Complexity to Translation Regulation

mBio ◽  
2017 ◽  
Vol 8 (6) ◽  
Author(s):  
N. Louise Glass
Keyword(s):  
Protein Synthesis ◽  
Cell Fate ◽  
Translation Initiation ◽  
Cellular Response ◽  
Open Reading Frames ◽  
Translation Regulation ◽  
Initiation Factors ◽  
Translation Initiation Factors ◽  
Upstream Open Reading Frames ◽  
Response To Stress

ABSTRACT The interplay between translation initiation, modification of translation initiation factors, and selection of start sites on mRNA for protein synthesis can play a regulatory role in the cellular response to stress, development, and cell fate in eukaryotic species by shaping the proteome. As shown by Ivanov et al. (mBio 8:e00844-17, 2017, https://doi.org/10.1128/mBio.00844-17 !), in the filamentous fungus Neurospora crassa, both upstream open reading frames (uORFs) and near-cognate start codons negatively or positively regulate the translation of the transcription factor CPC1 and production of CPC1 isoforms, which mediate the cellular response to amino acid starvation. Dissecting the physiological roles that differentiate cellular choice of translation initiation is an important parameter to understanding mechanisms that determine cell fate via gene regulation and protein synthesis.

scholarly journals Selective 40S footprinting reveals that scanning ribosomes remain cap-tethered in human cells

2019 ◽  
Author(s):  
Jonathan Bohlen ◽  
Kai Fenzl ◽  
Günter Kramer ◽  
Bernd Bukau ◽  
Aurelio A. Teleman
Keyword(s):  
Translation Initiation ◽  
Human Cells ◽  
Open Reading Frames ◽  
Translation Regulation ◽  
List Type ◽  
Translation Efficiency ◽  
Initiation Factors ◽  
Upstream Open Reading Frames

SUMMARYTranslation regulation occurs largely during initiation. Currently, translation initiation can be studied in vitro, but these systems lack features present in vivo and on endogenous mRNAs. Here we develop selective 40S footprinting for visualizing initiating 40S ribosomes on endogenous mRNAs in vivo. It pinpoints where on an mRNA initiation factors join the ribosome to act, and where they leave. We discover that in human cells most scanning ribosomes remain attached to the 5’ cap. Consequently, only one ribosome scans a 5’UTR at a time, and 5’UTR length affects translation efficiency. We discover that eIF3B, eIF4G1 and eIF4E remain on translating 80S ribosomes with a decay half-length of ∼12 codons. Hence ribosomes retain these initiation factors while translating short upstream Open Reading Frames (uORFs), providing an explanation for how ribosomes can re-initiate translation after uORFs in humans. This method will be of use for studying translation initiation mechanisms in vivo.HIGHLIGHTSSelective 40S FPing visualizes regulation of translation initiation on mRNAs in vivoScanning ribosomes are cap-tethered in human cellsOnly one ribosome scans a 5’UTR at a time in human cellsRibosomes retain eIFs during early translation, allowing reinitiation after uORFs

Subcellular localization of mRNA and factors involved in translation initiation

2008 ◽  
Vol 36 (4) ◽  
pp. 648-652 ◽  
Author(s):  
Nathaniel P. Hoyle ◽  
Mark P. Ashe
Keyword(s):  
Protein Synthesis ◽  
Subcellular Localization ◽  
Translation Initiation ◽  
Potential Functions ◽  
Present Review ◽  
Cellular Activity ◽  
Initiation Factors ◽  
Translation Initiation Factors

Both the process and synthesis of factors required for protein synthesis (or translation) account for a large proportion of cellular activity. In eukaryotes, the most complex and highly regulated phase of protein synthesis is that of initiation. For instance, across eukaryotes, at least 12 factors containing 22 or more proteins are involved, and there are several regulated steps. Recently, the localization of mRNA and factors involved in translation has received increased attention. The present review provides a general background to the subcellular localization of mRNA and translation initiation factors, and focuses on the potential functions of localized translation initiation factors. That is, as genuine sites for translation initiation, as repositories for factors and mRNA, and as sites of regulation.

MP60-12 FOLLICULIN TUMOR SUPPRESSOR BINDS TO TRANSLATION INITIATION FACTORS EIF2G & EIF5B AND SUPPRESSES PROTEIN SYNTHESIS

2017 ◽  
Vol 197 (4S) ◽  
Author(s):  
Meike Schneider ◽  
Taha Hagar ◽  
Katja Dinkelborg ◽  
Syed I.A. Bukhari ◽  
Axel Haferkamp ◽  
...  
Keyword(s):  
Protein Synthesis ◽  
Tumor Suppressor ◽  
Translation Initiation ◽  
Initiation Factors ◽  
Translation Initiation Factors

scholarly journals Translational specialization in pluripotency by RBPMS poises future lineage-decisions

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

scholarly journals eIF4G-driven translation initiation of downstream ORFs in mammalian cells

2020 ◽  
Vol 48 (18) ◽  
pp. 10441-10455
Author(s):  
Risa Nobuta ◽  
Kodai Machida ◽  
Misaki Sato ◽  
Satoshi Hashimoto ◽  
Yasuhito Toriumi ◽  
...  
Keyword(s):  
Translation Initiation ◽  
Mammalian Cells ◽  
Open Reading Frames ◽  
Translation System ◽  
Entry Site ◽  
Internal Ribosome Entry ◽  
Initiation Factors ◽  
Translation Initiation Factors ◽  
Genome Wide

Abstract Comprehensive genome-wide analysis has revealed the presence of translational elements in the 3′ untranslated regions (UTRs) of human transcripts. However, the mechanisms by which translation is initiated in 3′ UTRs and the physiological function of their products remain unclear. This study showed that eIF4G drives the translation of various downstream open reading frames (dORFs) in 3′ UTRs. The 3′ UTR of GCH1, which encodes GTP cyclohydrolase 1, contains an internal ribosome entry site (IRES) that initiates the translation of dORFs. An in vitro reconstituted translation system showed that the IRES in the 3′ UTR of GCH1 required eIF4G and conventional translation initiation factors, except eIF4E, for AUG-initiated translation of dORFs. The 3′ UTR of GCH1-mediated translation was resistant to the mTOR inhibitor Torin 1, which inhibits cap-dependent initiation by increasing eIF4E-unbound eIF4G. eIF4G was also required for the activity of various elements, including polyU and poliovirus type 2, a short element thought to recruit ribosomes by base-pairing with 18S rRNA. These findings indicate that eIF4G mediates translation initiation of various ORFs in mammalian cells, suggesting that the 3′ UTRs of mRNAs may encode various products.

scholarly journals Negative and Translation Termination-Dependent Positive Control of FLI-1 Protein Synthesis by Conserved Overlapping 5′ Upstream Open Reading Frames in Fli-1 mRNA

2000 ◽  
Vol 20 (9) ◽  
pp. 2959-2969 ◽  
Author(s):  
Sandrine Sarrazin ◽  
Joëlle Starck ◽  
Colette Gonnet ◽  
Alexandre Doubeikovski ◽  
Fabrice Melet ◽  
...  
Keyword(s):  
Protein Synthesis ◽  
Translation Initiation ◽  
Translation Termination ◽  
Mrna Translation ◽  
Positive Control ◽  
Open Reading Frames ◽  
Protein Isoforms ◽  
Erythroid Cell ◽  
Upstream Open Reading Frames ◽  
Reading Frames

ABSTRACT The proto-oncogene Fli-1 encodes a transcription factor of the ets family whose overexpression is associated with multiple virally induced leukemias in mouse, inhibits murine and avian erythroid cell differentiation, and induces drastic perturbations of early development in Xenopus. This study demonstrates the surprisingly sophisticated regulation of Fli-1 mRNA translation. We establish that two FLI-1 protein isoforms (of 51 and 48 kDa) detected by Western blotting in vivo are synthesized by alternative translation initiation through the use of two highly conserved in-frame initiation codons, AUG +1 and AUG +100. Furthermore, we show that the synthesis of these two FLI-1 isoforms is regulated by two short overlapping 5′ upstream open reading frames (uORF) beginning at two highly conserved upstream initiation codons, AUG −41 and GUG −37, and terminating at two highly conserved stop codons, UGA +35 and UAA +15. The mutational analysis of these two 5′ uORF revealed that each of them negatively regulates FLI-1 protein synthesis by precluding cap-dependent scanning to the 48- and 51-kDa AUG codons. Simultaneously, the translation termination of the two 5′ uORF appears to enhance 48-kDa protein synthesis, by allowing downstream reinitiation at the 48-kDa AUG codon, and 51-kDa protein synthesis, by allowing scanning ribosomes to pile up and consequently allowing upstream initiation at the 51-kDa AUG codon. To our knowledge, this is the first example of a cellular mRNA displaying overlapping 5′ uORF whose translation termination appears to be involved in the positive control of translation initiation at both downstream and upstream initiation codons.

scholarly journals eIF4GI links nutrient sensing by mTOR to cell proliferation and inhibition of autophagy

2008 ◽  
Vol 181 (2) ◽  
pp. 293-307 ◽  
Author(s):  
Francisco Ramírez-Valle ◽  
Steve Braunstein ◽  
Jiri Zavadil ◽  
Silvia C. Formenti ◽  
Robert J. Schneider
Keyword(s):  
Cell Proliferation ◽  
Nutrient Sensing ◽  
Open Reading Frames ◽  
Initiation Factor ◽  
Mitochondrial Activity ◽  
Breast Cancers ◽  
Initiation Factors ◽  
Translation Initiation Factors ◽  
Upstream Open Reading Frames ◽  
In Cells

Translation initiation factors have complex functions in cells that are not yet understood. We show that depletion of initiation factor eIF4GI only modestly reduces overall protein synthesis in cells, but phenocopies nutrient starvation or inhibition of protein kinase mTOR, a key nutrient sensor. eIF4GI depletion impairs cell proliferation, bioenergetics, and mitochondrial activity, thereby promoting autophagy. Translation of mRNAs involved in cell growth, proliferation, and bioenergetics were selectively inhibited by reduction of eIF4GI, as was the mRNA encoding Skp2 that inhibits p27, whereas catabolic pathway factors were increased. Depletion or overexpression of other eIF4G family members did not recapitulate these results. The majority of mRNAs that were translationally impaired with eIF4GI depletion were excluded from polyribosomes due to the presence of multiple upstream open reading frames and low mRNA abundance. These results suggest that the high levels of eIF4GI observed in many breast cancers might act to specifically increase proliferation, prevent autophagy, and release tumor cells from control by nutrient sensing.

scholarly journals Upstream Open Reading Frames Differentially Regulate Gene-specific Translation in the Integrated Stress Response

2016 ◽  
Vol 291 (33) ◽  
pp. 16927-16935 ◽  
Author(s):  
Sara K. Young ◽  
Ronald C. Wek
Keyword(s):  
Stress Response ◽  
Cell Fate ◽  
Translational Control ◽  
Open Reading Frames ◽  
Translation Regulation ◽  
Integrated Stress Response ◽  
Α Subunit ◽  
Stress Amelioration ◽  
Multiple Transcripts ◽  
Upstream Open Reading Frames

Translation regulation largely occurs during initiation, which features ribosome assembly onto mRNAs and selection of the translation start site. Short, upstream ORFs (uORFs) located in the 5′-leader of the mRNA can be selected for translation. Multiple transcripts associated with stress amelioration are preferentially translated through uORF-mediated mechanisms during activation of the integrated stress response (ISR) in which phosphorylation of the α subunit of eIF2 results in a coincident global reduction in translation initiation. This review presents key features of uORFs that serve to optimize translational control that is essential for regulation of cell fate in response to environmental stresses.

scholarly journals Mammalian stress granules and P bodies at a glance

2020 ◽  
Vol 133 (16) ◽  
pp. jcs242487 ◽  
Author(s):  
Claire L. Riggs ◽  
Nancy Kedersha ◽  
Pavel Ivanov ◽  
Paul Anderson
Keyword(s):  
Translation Initiation ◽  
Stress Granules ◽  
Detailed Knowledge ◽  
Processing Bodies ◽  
P Bodies ◽  
Initiation Factors ◽  
Translation Initiation Factors ◽  
Response To Stress ◽  
Cellular Compartments ◽  
Liquid Liquid Phase Separation

ABSTRACTStress granules (SGs) and processing bodies (PBs) are membraneless ribonucleoprotein-based cellular compartments that assemble in response to stress. SGs and PBs form through liquid–liquid phase separation that is driven by high local concentrations of key proteins and RNAs, both of which dynamically shuttle between the granules and the cytoplasm. SGs uniquely contain certain translation initiation factors and PBs are uniquely enriched with factors related to mRNA degradation and decay, although recent analyses reveal much broader protein commonality between these granules. Despite detailed knowledge of their composition and dynamics, the function of SGs and PBs remains poorly understood. Both, however, contain mRNAs, implicating their assembly in the regulation of RNA metabolism. SGs may also serve as hubs that rewire signaling events during stress. By contrast, PBs may constitute RNA storage centers, independent of mRNA decay. The aberrant assembly or disassembly of these granules has pathological implications in cancer, viral infection and neurodegeneration. Here, we review the current concepts regarding the formation, composition, dynamics, function and involvement in disease of SGs and PBs.

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