scholarly journals Translational regulation of non-autonomous mitochondrial stress response promotes longevity

2019 ◽  
Author(s):  
Jianfeng Lan ◽  
Jarod Rollins ◽  
Di Wu ◽  
Xiao Zang ◽  
Lina Zou ◽  
...  
Keyword(s):  
Stress Response ◽  
Cytochrome C ◽  
Ribosomal Proteins ◽  
Translational Regulation ◽  
Rna Binding ◽  
Mrna Translation ◽  
Translational Repression ◽  
List Type ◽  
Mitochondrial Stress ◽  
Ribosomal S6 Kinase

SummaryInhibition of mRNA translation delays aging, but the underlying mechanisms remain underexplored. Mutations in both DAF-2 (IGF-1 receptor) and RSKS-1 (ribosomal S6 kinase/S6K) cause synergistic lifespan extension in C. elegans. To understand the roles of S6K-mediated translational regulation in this process, we performed genome-wide translational profiling and genetic screens to identify genes that are not only regulated at the translational level in the daf-2 rsks-1 mutant, but also affect lifespan. Inhibition of CYC-2.1 (cytochrome c) in the germline significantly extends lifespan through non-autonomous activation of the mitochondrial unfolded protein response (UPRmt) and AMP-activated kinase (AMPK) in the metabolic tissue. Furthermore, the RNA-binding protein GLD-1-mediated translational repression of cytochrome c in the germline is important for the non-autonomous activation of UPRmt and synergistic longevity of the daf-2 rsks-1 mutant. Together, these results illustrate a translationally regulated non-autonomous mitochondrial stress response mechanism in the modulation of lifespan by insulin-like signaling and S6K.HighlightsLongevity of the daf-2 rsks-1 mutant is mediated by translational repression of ribosomal proteins and CYC-2.1/cytochrome c.Germline inhibition of cyc-2.1 non-autonomously activates UPRmt and AMPK to extend lifespan.GLD-1 represses germline cyc-2.1 translation in the daf-2 rsks-1 mutant.Translational regulation of cyc-2.1 and UPRmt contribute to the synergistic longevity of the daf-2 rsks-1 mutant.

Apontic binds the translational repressor Bruno and is implicated in regulation of oskar mRNA translation

Development ◽  
1999 ◽  
Vol 126 (6) ◽  
pp. 1129-1138 ◽  
Author(s):  
Y.S. Lie ◽  
P.M. Macdonald
Keyword(s):  
Translational Control ◽  
Untranslated Region ◽  
Rna Binding ◽  
Mrna Translation ◽  
Posterior Pole ◽  
Translational Repression ◽  
Yeast Two Hybrid ◽  
Functional Interaction ◽  
Translational Repressor ◽  
Two Hybrid

The product of the oskar gene directs posterior patterning in the Drosophila oocyte, where it must be deployed specifically at the posterior pole. Proper expression relies on the coordinated localization and translational control of the oskar mRNA. Translational repression prior to localization of the transcript is mediated, in part, by the Bruno protein, which binds to discrete sites in the 3′ untranslated region of the oskar mRNA. To begin to understand how Bruno acts in translational repression, we performed a yeast two-hybrid screen to identify Bruno-interacting proteins. One interactor, described here, is the product of the apontic gene. Coimmunoprecipitation experiments lend biochemical support to the idea that Bruno and Apontic proteins physically interact in Drosophila. Genetic experiments using mutants defective in apontic and bruno reveal a functional interaction between these genes. Given this interaction, Apontic is likely to act together with Bruno in translational repression of oskar mRNA. Interestingly, Apontic, like Bruno, is an RNA-binding protein and specifically binds certain regions of the oskar mRNA 3′ untranslated region.

scholarly journals IDH1 fine-tunes cap-dependent translation initiation

2019 ◽  
Vol 11 (10) ◽  
pp. 816-828 ◽  
Author(s):  
Lichao Liu ◽  
J Yuyang Lu ◽  
Fajin Li ◽  
Xudong Xing ◽  
Tong Li ◽  
...  
Keyword(s):  
Translation Initiation ◽  
Ribosomal Proteins ◽  
Rna Binding ◽  
Embryonic Stem ◽  
Mrna Translation ◽  
Fine Tuning ◽  
Start Codon ◽  
Metabolic Enzyme ◽  
Oxidative Decarboxylation ◽  
Dependent Manner

Abstract The metabolic enzyme isocitrate dehydrogenase 1 (IDH1) catalyzes the oxidative decarboxylation of isocitrate to α-ketoglutarate (α-KG). Its mutation often leads to aberrant gene expression in cancer. IDH1 was reported to bind thousands of RNA transcripts in a sequence-dependent manner; yet, the functional significance of this RNA-binding activity remains elusive. Here, we report that IDH1 promotes mRNA translation via direct associations with polysome mRNA and translation machinery. Comprehensive proteomic analysis in embryonic stem cells (ESCs) revealed striking enrichment of ribosomal proteins and translation regulators in IDH1-bound protein interactomes. We performed ribosomal profiling and analyzed mRNA transcripts that are associated with actively translating polysomes. Interestingly, knockout of IDH1 in ESCs led to significant downregulation of polysome-bound mRNA in IDH1 targets and subtle upregulation of ribosome densities at the start codon, indicating inefficient translation initiation upon loss of IDH1. Tethering IDH1 to a luciferase mRNA via the MS2-MBP system promotes luciferase translation, independently of the catalytic activity of IDH1. Intriguingly, IDH1 fails to enhance luciferase translation driven by an internal ribosome entry site. Together, these results reveal an unforeseen role of IDH1 in fine-tuning cap-dependent translation via the initiation step.

scholarly journals Csde1 cooperates with Strap to control translation of erythroid transcripts

2017 ◽  
Author(s):  
Kat S. Moore ◽  
Nurcan Yagci ◽  
Floris van Alphen ◽  
Alexander B. Meijer ◽  
Peter A.C. ‘t Hoen ◽  
...  
Keyword(s):  
Growth Factors ◽  
Environmental Conditions ◽  
Rna Splicing ◽  
Translational Regulation ◽  
Rna Binding ◽  
Protein Complexes ◽  
Rna Binding Protein ◽  
Mrna Translation ◽  
Hematopoietic Progenitors ◽  
Control Translation

AbstractErythropoiesis is regulated at many levels, including control of mRNA translation. Changing environmental conditions, such as hypoxia, or the availability of nutrients and growth factors, require a rapid response enacted by the enhanced or repressed translation of existing transcripts. Csde1 is an RNA-binding protein required for erythropoiesis and strongly upregulated in erythroblasts relative to other hematopoietic progenitors. The aim of this study is to identify the Csde1-containing protein complexes, and investigate their role in regulating the translation of Csde1-bound transcripts. We show that Strap, also called Unrip, was the protein most strongly associated with Csde1 in erythroblasts. Strap is a WD40 protein involved in signaling and RNA splicing, but its role is unknown when associated with Csde1. Reduced expression of Strap did not alter the pool of transcripts bound by Csde1. Instead, it reduced the mRNA and/or protein expression of several Csde1-bound transcript, that encode for proteins essential for translational regulation during hypoxia, such as Hmbs, eIF4g3 and Pabpc4. Also affected by Strap knockdown were Vim, a Gata-1 target crucial for erythrocyte enucleation, and Elavl1, which stabilizes Gata-1 mRNA. Thus, we found that the Csde1/Strap complex is at the crossroad of multiple pathways governing translation in erythroblasts.

scholarly journals Dynamics of hunchback translation in real time and at single mRNA resolution in the Drosophila embryo

Development ◽  
2021 ◽  
pp. dev.196121
Author(s):  
Daisy J. Vinter ◽  
Caroline Hoppe ◽  
Thomas G. Minchington ◽  
Catherine Sutcliffe ◽  
Hilary L. Ashe
Keyword(s):  
Single Molecule ◽  
Translational Regulation ◽  
Mrna Translation ◽  
Drosophila Embryo ◽  
Translational Repression ◽  
Expression Domain ◽  
Culture Cells ◽  
Spatiotemporal Regulation ◽  
Developmental Patterning ◽  
Anterior Posterior

The Hunchback (Hb) transcription factor is critical for anterior-posterior patterning of the Drosophila embryo. Despite the maternal hb mRNA acting as a paradigm for translational regulation, due to its repression in the posterior of the embryo, little is known about the translatability of zygotically transcribed hb mRNAs. Here we adapt the SunTag system, developed for imaging translation at single mRNA resolution in tissue culture cells, to the Drosophila embryo to study the translation dynamics of zygotic hb mRNAs. Using single-molecule imaging in fixed and live embryos, we provide evidence for translational repression of zygotic SunTag-hb mRNAs. While the proportion of SunTag-hb mRNAs translated is initially uniform, translation declines from the anterior over time until it becomes restricted to a posterior band in the expression domain. We discuss how regulated hb mRNA translation may help establish the sharp Hb expression boundary, which is a model for precision and noise during developmental patterning. Overall, our data show how use of the SunTag method on fixed and live embryos is a powerful combination for elucidating spatiotemporal regulation of mRNA translation in Drosophila.

scholarly journals Multi-omics analysis identifies ATF4 as a key regulator of the mitochondrial stress response in mammals

2017 ◽  
Vol 216 (7) ◽  
pp. 2027-2045 ◽  
Author(s):  
Pedro M. Quirós ◽  
Miguel A. Prado ◽  
Nicola Zamboni ◽  
Davide D’Amico ◽  
Robert W. Williams ◽  
...  
Keyword(s):  
Stress Response ◽  
Mitochondrial Function ◽  
Mammalian Cells ◽  
Ribosomal Proteins ◽  
Cellular Metabolism ◽  
Mitochondrial Diseases ◽  
Mitochondrial Translation ◽  
Mitochondrial Stress ◽  
Main Regulator

Mitochondrial stress activates a mitonuclear response to safeguard and repair mitochondrial function and to adapt cellular metabolism to stress. Using a multiomics approach in mammalian cells treated with four types of mitochondrial stressors, we identify activating transcription factor 4 (ATF4) as the main regulator of the stress response. Surprisingly, canonical mitochondrial unfolded protein response genes mediated by ATF5 are not activated. Instead, ATF4 activates the expression of cytoprotective genes, which reprogram cellular metabolism through activation of the integrated stress response (ISR). Mitochondrial stress promotes a local proteostatic response by reducing mitochondrial ribosomal proteins, inhibiting mitochondrial translation, and coupling the activation of the ISR with the attenuation of mitochondrial function. Through a trans–expression quantitative trait locus analysis, we provide genetic evidence supporting a role for Fh1 in the control of Atf4 expression in mammals. Using gene expression data from mice and humans with mitochondrial diseases, we show that the ATF4 pathway is activated in vivo upon mitochondrial stress. Our data illustrate the value of a multiomics approach to characterize complex cellular networks and provide a versatile resource to identify new regulators of mitochondrial-related diseases.

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 Processing Body Formation Limits Proinflammatory Cytokine Synthesis in Endotoxin-Tolerant Monocytes and Murine Septic Macrophages

2015 ◽  
Vol 7 (6) ◽  
pp. 572-583 ◽  
Author(s):  
Clara McClure ◽  
Laura Brudecki ◽  
Zhi Q. Yao ◽  
Charles E. McCall ◽  
Mohamed El Gazzar
Keyword(s):  
Protein Synthesis ◽  
Rna Binding ◽  
Mrna Translation ◽  
Endotoxin Tolerance ◽  
Translational Repression ◽  
Binding Motif ◽  
Body Formation ◽  
Translational Repressor ◽  
Protein Levels ◽  
Repressor Complex

An anti-inflammatory phenotype with pronounced immunosuppression develops during sepsis, during which time neutrophils and monocytes/macrophages limit their Toll-like receptor 4 responses to bacterial lipopolysaccharide (LPS/endotoxin). We previously reported that during this endotoxin-tolerant state, distinct signaling pathways differentially repress transcription and translation of proinflammatory cytokines such as TNFα and IL-6. Sustained endotoxin tolerance contributes to sepsis mortality. While transcription repression requires chromatin modifications, a translational repressor complex of Argonaute 2 (Ago2) and RNA-binding motif protein 4 (RBM4), which bind the 3′-UTR of TNFα and IL-6 mRNA, limits protein synthesis. Here, we show that Dcp1 supports the assembly of the Ago2 and RBM4 repressor complex into cytoplasmic processing bodies (p-bodies) in endotoxin-tolerant THP-1 human monocytes following stimulation with LPS, resulting in translational repression and limiting protein synthesis. Importantly, this translocation process is reversed by Dcp1 knockdown, which restores TNFα and IL-6 protein levels. We also find this translational repression mechanism in primary macrophages of septic mice. Because p-body formation is a critical step in mRNA translation repression, we conclude that Dcp1 is a major component of the translational repression machinery of endotoxin tolerance and may contribute to sepsis outcome.

scholarly journals Regulation of mRNA translation during mitosis

eLife ◽  
2015 ◽  
Vol 4 ◽  
Author(s):  
Marvin E Tanenbaum ◽  
Noam Stern-Ginossar ◽  
Jonathan S Weissman ◽  
Ronald D Vale
Keyword(s):  
Protein Function ◽  
Translational Regulation ◽  
Mrna Translation ◽  
Ribosome Profiling ◽  
Translational Repression ◽  
Anaphase Promoting Complex ◽  
Mitotic Entry ◽  
Primary Mechanism ◽  
Specific Regulation ◽  
Translational Mechanisms

Passage through mitosis is driven by precisely-timed changes in transcriptional regulation and protein degradation. However, the importance of translational regulation during mitosis remains poorly understood. Here, using ribosome profiling, we find both a global translational repression and identified ∼200 mRNAs that undergo specific translational regulation at mitotic entry. In contrast, few changes in mRNA abundance are observed, indicating that regulation of translation is the primary mechanism of modulating protein expression during mitosis. Interestingly, 91% of the mRNAs that undergo gene-specific regulation in mitosis are translationally repressed, rather than activated. One of the most pronounced translationally-repressed genes is Emi1, an inhibitor of the anaphase promoting complex (APC) which is degraded during mitosis. We show that full APC activation requires translational repression of Emi1 in addition to its degradation. These results identify gene-specific translational repression as a means of controlling the mitotic proteome, which may complement post-translational mechanisms for inactivating protein function.

scholarly journals Ribosomal protein S7 ubiquitination during ER stress in yeast is associated with selective mRNA translation and stress outcome

2020 ◽  
Vol 10 (1) ◽  
Author(s):  
Yasuko Matsuki ◽  
Yoshitaka Matsuo ◽  
Yu Nakano ◽  
Shintaro Iwasaki ◽  
Hideyuki Yoko ◽  
...  
Keyword(s):  
Er Stress ◽  
Ribosomal Protein ◽  
Translational Control ◽  
Ribosomal Proteins ◽  
Translational Regulation ◽  
Mrna Translation ◽  
Ribosome Profiling ◽  
Independent Manner ◽  
Eif2α Phosphorylation ◽  
The Unfolded Protein Response

AbstracteIF2α phosphorylation-mediated translational regulation is crucial for global translation repression by various stresses, including the unfolded protein response (UPR). However, translational control during UPR has not been demonstrated in yeast. This study investigated ribosome ubiquitination-mediated translational controls during UPR. Tunicamycin-induced ER stress enhanced the levels of ubiquitination of the ribosomal proteins uS10, uS3 and eS7. Not4-mediated monoubiquitination of eS7A was required for resistance to tunicamycin, whereas E3 ligase Hel2-mediated ubiquitination of uS10 was not. Ribosome profiling showed that the monoubiquitination of eS7A was crucial for translational regulation, including the upregulation of the spliced form of HAC1 (HAC1i) mRNA and the downregulation of Histidine triad NucleoTide-binding 1 (HNT1) mRNA. Downregulation of the deubiquitinating enzyme complex Upb3-Bre5 increased the levels of ubiquitinated eS7A during UPR in an Ire1-independent manner. These findings suggest that the monoubiquitination of ribosomal protein eS7A plays a crucial role in translational controls during the ER stress response in yeast.

scholarly journals Ribosomal protein S7 ubiquitination during ER stress in yeast is associated with selective mRNA translation and stress outcome

2020 ◽  
Author(s):  
Yasuko Matsuki ◽  
Yoshitaka Matsuo ◽  
Yu Nakano ◽  
Shintaro Iwasaki ◽  
Hideyuki Yoko ◽  
...  
Keyword(s):  
Er Stress ◽  
Ribosomal Protein ◽  
Translational Control ◽  
Ribosomal Proteins ◽  
Translational Regulation ◽  
Mrna Translation ◽  
Ribosome Profiling ◽  
Independent Manner ◽  
Eif2α Phosphorylation ◽  
The Unfolded Protein Response

ABSTRACTeIF2α phosphorylation-mediated translational regulation is crucial for global translation repression by various stresses, including the unfolded protein response (UPR). However, translational control during UPR has not been demonstrated in yeast. This study investigated ribosome ubiquitination-mediated translational controls during UPR. Tunicamycin-induced ER stress enhanced the levels of ubiquitination of the ribosomal proteins uS10, uS3 and eS7. Not4-mediated monoubiquitination of eS7A was required for resistance to tunicamycin, whereas E3 ligase Hel2-mediated ubiquitination of uS10 was not. Ribosome profiling showed that the monoubiquitination of eS7A was crucial for translational regulation, including the upregulation of the spliced form of HAC1 (HAC1i) mRNA and the downregulation of Histidine triad NucleoTide-binding 1 (HNT1) mRNA. Downregulation of the deubiquitinating enzyme complex Upb3-Bre5 increased the levels of ubiquitinated eS7A during UPR in an Ire1-independent manner. These findings suggest that the monoubiquitination of ribosomal protein eS7A plays a crucial role in translational controls during the ER stress response in yeast.

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