Signalling to translation: how signal transduction pathways control the protein synthetic machinery

2007 ◽  
Vol 403 (2) ◽  
pp. 217-234 ◽  
Author(s):  
Christopher G. Proud
Keyword(s):  
Protein Synthesis ◽  
Protein Kinases ◽  
Mammalian Cells ◽  
Rna Binding ◽  
Rna Binding Proteins ◽  
Mrna Translation ◽  
Signalling Pathways ◽  
Cancer Tissue ◽  
Energy Status ◽  
Specific Mrnas

Recent advances in our understanding of both the regulation of components of the translational machinery and the upstream signalling pathways that modulate them have provided important new insights into the mechanisms by which hormones, growth factors, nutrients and cellular energy status control protein synthesis in mammalian cells. The importance of proper control of mRNA translation is strikingly illustrated by the fact that defects in this process or its control are implicated in a number of disease states, such as cancer, tissue hypertrophy and neurodegeneration. Signalling pathways such as those involving mTOR (mammalian target of rapamycin) and mitogen-activated protein kinases modulate the phosphorylation of translation factors, the activities of the protein kinases that act upon them and the association of RNA-binding proteins with specific mRNAs. These effects contribute both to the overall control of protein synthesis (which is linked to cell growth) and to the modulation of the translation or stability of specific mRNAs. However, important questions remain about both the contributions of individual regulatory events to the control of general protein synthesis and the mechanisms by which the translation of specific mRNAs is controlled.

scholarly journals Receptor-specific interactome as a hub for rapid cue-induced selective translation in axons

2019 ◽  
Author(s):  
Max Koppers ◽  
Roberta Cagnetta ◽  
Toshiaki Shigeoka ◽  
Lucia C.S. Wunderlich ◽  
Sixian Zhao ◽  
...  
Keyword(s):  
Rna Binding ◽  
Rna Binding Proteins ◽  
Axon Growth ◽  
Mrna Translation ◽  
Local Translation ◽  
Simultaneous Exposure ◽  
Surface Receptors ◽  
Guidance Cue ◽  
Selective Translation ◽  
Specific Mrnas

AbstractDuring neuronal wiring, extrinsic cues trigger the local translation of specific mRNAs in axons via cell surface receptors. The coupling of ribosomes to receptors has been proposed as a mechanism linking signals to local translation but it is not known how broadly this mechanism operates, nor whether it can selectively regulate mRNA translation. We report that receptor-ribosome coupling is employed by multiple guidance cue receptors and this interaction is mRNA-dependent. We find that different receptors bind to distinct sets of mRNAs and RNA-binding proteins. Cue stimulation induces rapid dissociation of ribosomes from receptors and the selective translation of receptor-specific mRNAs in retinal axon growth cones. Further, we show that receptor-ribosome dissociation and cue-induced selective translation are inhibited by simultaneous exposure to translation-repressive cues, suggesting a novel mode of signal integration. Our findings reveal receptor-specific interactomes and provide a general model for the rapid, localized and selective control of cue-induced translation.

scholarly journals Receptor-specific interactome as a hub for rapid cue-induced selective translation in axons

eLife ◽  
2019 ◽  
Vol 8 ◽  
Author(s):  
Max Koppers ◽  
Roberta Cagnetta ◽  
Toshiaki Shigeoka ◽  
Lucia CS Wunderlich ◽  
Pedro Vallejo-Ramirez ◽  
...  
Keyword(s):  
Rna Binding ◽  
Rna Binding Proteins ◽  
Mrna Translation ◽  
Retinal Ganglion ◽  
Local Translation ◽  
Surface Receptors ◽  
Guidance Cue ◽  
Extrinsic Cues ◽  
Selective Translation ◽  
Specific Mrnas

Extrinsic cues trigger the local translation of specific mRNAs in growing axons via cell surface receptors. The coupling of ribosomes to receptors has been proposed as a mechanism linking signals to local translation but it is not known how broadly this mechanism operates, nor whether it can selectively regulate mRNA translation. We report that receptor-ribosome coupling is employed by multiple guidance cue receptors and this interaction is mRNA-dependent. We find that different receptors associate with distinct sets of mRNAs and RNA-binding proteins. Cue stimulation of growing Xenopus retinal ganglion cell axons induces rapid dissociation of ribosomes from receptors and the selective translation of receptor-specific mRNAs. Further, we show that receptor-ribosome dissociation and cue-induced selective translation are inhibited by co-exposure to translation-repressive cues, suggesting a novel mode of signal integration. Our findings reveal receptor-specific interactomes and suggest a generalizable model for cue-selective control of the local proteome.

scholarly journals CLUH interactome reveals an association to SPAG5 and a proximity to the translation of mitochondrial protein

2021 ◽  
Author(s):  
Mickaële Hemono ◽  
Alexandre Haller ◽  
Johana Chicher ◽  
Anne-Marie Duchêne ◽  
Richard Patryk Ngondo
Keyword(s):  
Mammalian Cells ◽  
Rna Binding ◽  
Rna Binding Proteins ◽  
Mitochondrial Protein ◽  
Embryonic Stem ◽  
Nuclear Genome ◽  
Mrna Translation ◽  
Mitochondrial Proteins ◽  
Molecular Function ◽  
First Time

Mitochondria require thousands of proteins to fulfil their essential function in energy production and other fundamental biological processes. These proteins are mostly encoded by the nuclear genome, translated in the cytoplasm before being imported into the organelle. RNA binding proteins (RBPs) are central players in the regulation of this process by affecting mRNA translation, stability or localization. CLUH is an RBP recognizing specifically mRNAs coding for mitochondrial proteins, but its precise molecular function and interacting partners remain undiscovered in mammals. Here we reveal for the first time CLUH interactome in mammalian cells. Using both co-IP and BioID proximity-labeling approaches, we identify novel molecular partners interacting stably or transiently with CLUH in HCT116 cells and mouse embryonic stem cells. We reveal a stable RNA-independent interaction of CLUH with itself and with SPAG5 in cytosolic granular structures. More importantly, we uncover an unexpected proximity of CLUH to mitochondrial proteins and their cognate mRNAs in the cytosol. Additionally, our data highlight the importance of CLUH TPR domain for its interactions with both proteins and mRNAs. Overall, through the analysis of CLUH interactome, our study sheds a new light on CLUH molecular function by highlighting its association to the translation and subcellular localization of some mRNAs coding for mitochondrial proteins.

scholarly journals Quantitative Proteomics Links the LRRC59 Interactome to mRNA Translation on the ER Membrane

2020 ◽  
Vol 19 (11) ◽  
pp. 1826-1849
Author(s):  
Molly M. Hannigan ◽  
Alyson M. Hoffman ◽  
J. Will Thompson ◽  
Tianli Zheng ◽  
Christopher V. Nicchitta
Keyword(s):  
Protein Synthesis ◽  
Steady State ◽  
Membrane Protein ◽  
Binding Proteins ◽  
Rna Binding ◽  
Rna Binding Proteins ◽  
Mrna Translation ◽  
Integral Membrane Protein ◽  
Translation Factors ◽  
Er Membrane

Protein synthesis on the endoplasmic reticulum (ER) requires the dynamic coordination of numerous cellular components. Together, resident ER membrane proteins, cytoplasmic translation factors, and both integral membrane and cytosolic RNA-binding proteins operate in concert with membrane-associated ribosomes to facilitate ER-localized translation. Little is known, however, regarding the spatial organization of ER-localized translation. This question is of growing significance as it is now known that ER-bound ribosomes contribute to secretory, integral membrane, and cytosolic protein synthesis alike. To explore this question, we utilized quantitative proximity proteomics to identify neighboring protein networks for the candidate ribosome interactors SEC61β (subunit of the protein translocase), RPN1 (oligosaccharyltransferase subunit), SEC62 (translocation integral membrane protein), and LRRC59 (ribosome binding integral membrane protein). Biotin labeling time course studies of the four BioID reporters revealed distinct labeling patterns that intensified but only modestly diversified as a function of labeling time, suggesting that the ER membrane is organized into discrete protein interaction domains. Whereas SEC61β and RPN1 reporters identified translocon-associated networks, SEC62 and LRRC59 reporters revealed divergent protein interactomes. Notably, the SEC62 interactome is enriched in redox-linked proteins and ER luminal chaperones, with the latter likely representing proximity to an ER luminal chaperone reflux pathway. In contrast, the LRRC59 interactome is highly enriched in SRP pathway components, translation factors, and ER-localized RNA-binding proteins, uncovering a functional link between LRRC59 and mRNA translation regulation. Importantly, analysis of the LRRC59 interactome by native immunoprecipitation identified similar protein and functional enrichments. Moreover, [35S]-methionine incorporation assays revealed that siRNA silencing of LRRC59 expression reduced steady state translation levels on the ER by ca. 50%, and also impacted steady state translation levels in the cytosol compartment. Collectively, these data reveal a functional domain organization for the ER and identify a key role for LRRC59 in the organization and regulation of local translation.

scholarly journals Post-transcriptional control of gene expression following stress: the role of RNA-binding proteins

2017 ◽  
Vol 45 (4) ◽  
pp. 1007-1014 ◽  
Author(s):  
Robert Harvey ◽  
Veronica Dezi ◽  
Mariavittoria Pizzinga ◽  
Anne E. Willis
Keyword(s):  
Protein Synthesis ◽  
Mammalian Cells ◽  
Cellular Response ◽  
Transcriptional Control ◽  
Binding Proteins ◽  
Rna Binding ◽  
Rna Binding Proteins ◽  
Major Influence ◽  
Functional Protein ◽  
Control Of Gene Expression

The ability of mammalian cells to modulate global protein synthesis in response to cellular stress is essential for cell survival. While control of protein synthesis is mediated by the regulation of eukaryotic initiation and elongation factors, RNA-binding proteins (RBPs) provide a crucial additional layer to post-transcriptional regulation. RBPs bind specific RNA through conserved RNA-binding domains and ensure that the information contained within the genome and transcribed in the form of RNA is exported to the cytoplasm, chemically modified, and translated prior to folding into a functional protein. Thus, this group of proteins, through mediating translational reprogramming, spatial reorganisation, and chemical modification of RNA molecules, have a major influence on the robust cellular response to external stress and toxic injury.

scholarly journals The interactome of CLUH reveals its association to SPAG5 and its co-translational proximity to mitochondrial proteins

BMC Biology ◽  
2022 ◽  
Vol 20 (1) ◽  
Author(s):  
Mickaële Hémono ◽  
Alexandre Haller ◽  
Johana Chicher ◽  
Anne-Marie Duchêne ◽  
Richard Patryk Ngondo
Keyword(s):  
Mammalian Cells ◽  
Rna Binding ◽  
Rna Binding Proteins ◽  
Embryonic Stem ◽  
Nuclear Genome ◽  
Mrna Translation ◽  
Mitochondrial Proteins ◽  
Molecular Function ◽  
First Time ◽  
Tpr Domain

Abstract Background Mitochondria require thousands of proteins to fulfill their essential function in energy production and other fundamental biological processes. These proteins are mostly encoded by the nuclear genome, translated in the cytoplasm before being imported into the organelle. RNA binding proteins (RBPs) are central players in the regulation of this process by affecting mRNA translation, stability, or localization. CLUH is an RBP recognizing specifically mRNAs coding for mitochondrial proteins, but its precise molecular function and interacting partners remain undiscovered in mammals. Results Here we reveal for the first time CLUH interactome in mammalian cells. Using both co-IP and BioID proximity-labeling approaches, we identify novel molecular partners interacting stably or transiently with CLUH in HCT116 cells and mouse embryonic stem cells. We reveal stable RNA-independent interactions of CLUH with itself and with SPAG5 in cytosolic granular structures. More importantly, we uncover an unexpected proximity of CLUH to mitochondrial proteins and their cognate mRNAs in the cytosol. We show that this interaction occurs during the process of active translation and is dependent on CLUH TPR domain. Conclusions Overall, through the analysis of CLUH interactome, our study sheds a new light on CLUH molecular function by revealing new partners and by highlighting its link to the translation and subcellular localization of some mRNAs coding for mitochondrial proteins.

scholarly journals High-Throughput Translational Profiling with riboPLATE-seq

2019 ◽  
Author(s):  
Jordan B. Metz ◽  
Nicholas J. Hornstein ◽  
Sohani Das Sharma ◽  
Jeremy Worley ◽  
Peter A. Sims
Keyword(s):  
Protein Synthesis ◽  
Protein Kinases ◽  
High Throughput ◽  
Binding Proteins ◽  
Rna Binding ◽  
Rna Binding Proteins ◽  
Library Preparation ◽  
Translational Machinery ◽  
Technological Limitations ◽  
Ribosome Association

ABSTRACTProtein synthesis is dysregulated in many diseases, but we lack a systems-level picture of how signaling molecules and RNA binding proteins interact with the translational machinery, largely due to technological limitations. Here we present riboPLATE-seq, a scalable method for generating paired libraries of ribosome-associated and total mRNA. As an extension of the PLATE-seq protocol, riboPLATE-seq utilizes barcoded primers for pooled library preparation, but additionally leverages rRNA immunoprecipitation on whole polysomes to measure ribosome association (RA). We demonstrate the performance of riboPLATE-seq and its utility in detecting translational alterations induced by inhibition of protein kinases.

scholarly journals Quantitative proteomics links the LRRC59 interactome to mRNA translation on the ER membrane

2020 ◽  
Author(s):  
Molly M. Hannigan ◽  
Alyson M. Hoffman ◽  
J. Will Thompson ◽  
Tianli Zheng ◽  
Christopher V. Nicchitta
Keyword(s):  
Protein Synthesis ◽  
Membrane Proteins ◽  
Redox Regulation ◽  
Binding Proteins ◽  
Rna Binding ◽  
Rna Binding Proteins ◽  
Mrna Translation ◽  
Functional Domain ◽  
Translation Factors ◽  
Er Membrane

AbstractProtein synthesis on the endoplasmic reticulum (ER) requires the dynamic coordination of resident membrane proteins and cytoplasmic translation factors. While ER membrane proteins functioning in ribosome association, mRNA anchoring, and protein translocation, have been identified, little is known regarding the higher order organization of ER-localized translation. Here we utilized proximity proteomics to identify neighboring protein networks for the ribosome interactors SEC61β, RPN1, SEC62, and LRRC59. Whereas the SEC61β and RPN1 BioID reporters revealed translocon-associated networks, the SEC62 and LRRC59 reporters identified divergent interactome networks of previously unexplored functions. Notably, the SEC62 interactome is enriched in redox-linked proteins and ER luminal chaperones, whereas the LRRC59 interactome is enriched in SRP pathway components, translation factors, and ER-localized RNA-binding proteins. Analysis of the LRRC59 interactome by native immunoprecipitation identified similar protein and functional enrichments. Combined, these data reveal a functional domain organization for the ER and suggest a key role for LRRC59 in the organization of mRNA translation on the ER.SummaryHannigan et al. characterize the protein interactomes of four ER ribosome-binding proteins, providing evidence that ER-bound ribosomes reside in distinct molecular environments. Their data link SEC62 to ER redox regulation and chaperone trafficking, and suggest a role for LRRC59 in SRP-coupled protein synthesis.

mTORC1 signalling and mRNA translation

2009 ◽  
Vol 37 (1) ◽  
pp. 227-231 ◽  
Author(s):  
Christopher G. Proud
Keyword(s):  
Protein Synthesis ◽  
Growth Factors ◽  
Protein Kinases ◽  
Mammalian Target Of Rapamycin ◽  
Mrna Translation ◽  
Protein Accumulation ◽  
Anabolic Hormones ◽  
Cell Functions ◽  
Translation Factors ◽  
Specific Mrnas

Signalling through mTORC1 (mammalian target of rapamycin complex 1) is important in controlling many cell functions, including protein synthesis, which it activates. mTORC1 signalling is activated by stimuli which promote protein accumulation such as anabolic hormones, growth factors and hypertrophic stimuli. mTORC1 signalling regulates several components of the protein synthetic machinery, including initiation and elongation factors, protein kinases which phosphorylate the ribosome and/or translation factors, and the translation of specific mRNAs. However, there are still important gaps in our understanding of the actions of mTORC1 and the relative contributions that different targets of mTORC1 make to the activation of protein synthesis remain to be established.

scholarly journals Connecting cis-elements and trans-factors with mechanisms of developmental regulation of mRNA translation in meiotic and haploid mammalian spermatogenic cells

Reproduction ◽  
2013 ◽  
Vol 146 (1) ◽  
pp. R1-R19 ◽  
Author(s):  
Kenneth C Kleene
Keyword(s):  
Translational Control ◽  
Mammalian Cells ◽  
Rna Binding ◽  
Rna Binding Proteins ◽  
Developmental Regulation ◽  
Mrna Translation ◽  
Spermatogenic Cells ◽  
Mrna Targets ◽  
Translational Activity ◽  
Specific Regulation

mRNA-specific regulation of translational activity plays major roles in directing the development of meiotic and haploid spermatogenic cells in mammals. Although many RNA-binding proteins (RBPs) have been implicated in normal translational control and sperm development, little is known about the keystone of the mechanisms: the interactions of RBPs and microRNAs withcis-elements in mRNA targets. The problems in connecting factors and elements with translational control originate in the enormous complexity of post-transcriptional regulation in mammalian cells. This creates confusion as to whether factors have direct or indirect and large or small effects on the translation of specific mRNAs. This review argues that gene knockouts, heterologous systems, and overexpression of factors cannot provide convincing answers to these questions. As a result, the mechanisms involving well-studied mRNAs (Ddx4/Mvh,Prm1,Prm2, andSycp3) and factors (DICER1, CPEB1, DAZL, DDX4/MVH, DDX25/GRTH, translin, and ELAV1/HuR) are incompletely understood. By comparison, mutations in elements can be used to define the importance of specific pathways in regulating individual mRNAs. However, few elements have been studied, because the only reliable system to analyze mutations in elements, transgenic mice, is considered impractical. This review describes advances that may facilitate identification of the direct targets of RBPs and analysis of mutations incis-elements. The importance of upstream reading frames in the developmental regulation of mRNA translation in spermatogenic cells is also documented.

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