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Cap-dependent translation

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https://www.readbyqxmd.com/read/29323119/cug-initiation-and-frameshifting-enable-production-of-dipeptide-repeat-proteins-from-als-ftd-c9orf72-transcripts
#1
Ricardos Tabet, Laure Schaeffer, Fernande Freyermuth, Melanie Jambeau, Michael Workman, Chao-Zong Lee, Chun-Chia Lin, Jie Jiang, Karen Jansen-West, Hussein Abou-Hamdan, Laurent Désaubry, Tania Gendron, Leonard Petrucelli, Franck Martin, Clotilde Lagier-Tourenne
Expansion of G4C2 repeats in the C9ORF72 gene is the most prevalent inherited form of amyotrophic lateral sclerosis and frontotemporal dementia. Expanded transcripts undergo repeat-associated non-AUG (RAN) translation producing dipeptide repeat proteins from all reading frames. We determined cis-factors and trans-factors influencing translation of the human C9ORF72 transcripts. G4C2 translation operates through a 5'-3' cap-dependent scanning mechanism, requiring a CUG codon located upstream of the repeats and an initiator Met-tRNAMeti...
January 11, 2018: Nature Communications
https://www.readbyqxmd.com/read/29298542/the-role-of-alpha7-nicotinic-acetylcholine-receptors-in-inflammatory-bowel-disease-involvement-of-different-cellular-pathways
#2
Mohammad Seyedabadi, Reza Rahimian, Jean-Eric Ghia
Autonomic imbalance plays a pivotal role in the pathophysiology of inflammatory bowel diseases (IBD). The central nervous system (CNS) cooperates dynamically with the immune system to regulate inflammation through humoral and neural pathways. In particular, acetylcholine (Ach), the main neurotransmitter in the vagus nerve, decreases the production of pro-inflammatory cytokines through a mechanism dependent on the α7 nicotinic Ach receptors (α7nAChRs). Areas covered: Here, we review the evidence for involvement of the cholinergic anti-inflammatory pathway (CAP) in IBD...
January 3, 2018: Expert Opinion on Therapeutic Targets
https://www.readbyqxmd.com/read/29298432/characterizing-zc3h18-a-multi-domain-protein-at-the-interface-of-rna-production-and-destruction-decisions
#3
Kinga Winczura, Manfred Schmid, Claudia Iasillo, Kelly R Molloy, Lea Mørch Harder, Jens S Andersen, John LaCava, Torben Heick Jensen
Nuclear RNA metabolism is influenced by protein complexes connecting to both RNA-productive and -destructive pathways. The ZC3H18 protein binds the cap-binding complex (CBC), universally present on capped RNAs, while also associating with the nuclear exosome targeting (NEXT) complex, linking to RNA decay. To dissect ZC3H18 function, we conducted interaction screening and mutagenesis of the protein, which revealed a phosphorylation-dependent isoform. Surprisingly, the modified region of ZC3H18 associates with core histone proteins...
January 2, 2018: Cell Reports
https://www.readbyqxmd.com/read/29298419/oxygen-sensitive-remodeling-of-central-carbon-metabolism-by-archaic-eif5b
#4
J J David Ho, Nathan C Balukoff, Grissel Cervantes, Petrice D Malcolm, Jonathan R Krieger, Stephen Lee
The eukaryotic translation initiation factor 5B (eIF5B) is a homolog of IF2, an ancient translation factor that enables initiator methionine-tRNAiMet (met-tRNAiMet) loading on prokaryotic ribosomes. While it can be traced back to the last universal common ancestor, eIF5B is curiously dispensable in modern aerobic yeast and mammalian cells. Here, we show that eIF5B is an essential element of the cellular hypoxic cap-dependent protein synthesis machinery. System-wide interrogation of dynamic translation machineries by MATRIX (mass spectrometry analysis of active translation factors using ribosome density fractionation and isotopic labeling experiments) demonstrated augmented eIF5B activity in hypoxic translating ribosomes...
January 2, 2018: Cell Reports
https://www.readbyqxmd.com/read/29295980/inhibition-of-poly-a-binding-protein-with-a-synthetic-rna-mimic-reduces-pain-sensitization-in-mice
#5
Paulino Barragán-Iglesias, Tzu-Fang Lou, Vandita D Bhat, Salim Megat, Michael D Burton, Theodore J Price, Zachary T Campbell
Nociceptors rely on cap-dependent translation to rapidly induce protein synthesis in response to pro-inflammatory signals. Comparatively little is known regarding the role of the regulatory factors bound to the 3' end of mRNA in nociceptor sensitization. Poly(A)-binding protein (PABP) stimulates translation initiation by bridging the Poly(A) tail to the eukaryotic initiation factor 4F complex associated with the mRNA cap. Here, we use unbiased assessment of PABP binding specificity to generate a chemically modified RNA-based competitive inhibitor of PABP...
January 2, 2018: Nature Communications
https://www.readbyqxmd.com/read/29288414/trypanosoma-brucei-eif4e2-cap-binding-protein-binds-a-homolog-of-the-histone-mrna-stem-loop-binding-protein
#6
Eden R Freire, Danielle M N Moura, Maria J R Bezerra, Camila C Xavier, Mariana C Morais-Sobral, Ajay A Vashisht, Antonio M Rezende, James A Wohlschlegel, Nancy R Sturm, Osvaldo P de Melo Neto, David A Campbell
Trypanosomatids are parasitic protozoans characterized by several unique structural and metabolic processes that include exquisite mechanisms associated with gene expression and regulation. During the initiation of protein synthesis, for instance, mRNA selection for translation seems to be mediated by different eIF4F-like complexes, which may play a significant role in parasite adaptation to different hosts. In eukaryotes, the heterotrimeric eIF4F complex (formed by eIF4E, eIF4G, and eIF4A) mediates mRNA recognition and ribosome binding and participates in various translation regulatory events...
December 29, 2017: Current Genetics
https://www.readbyqxmd.com/read/29258862/broad-spectrum-antiviral-activity-of-the-eif4a-inhibitor-silvestrol-against-corona-and-picornaviruses
#7
Christin Müller, Falk W Schulte, Kerstin Lange-Grünweller, Wiebke Obermann, Ramakanth Madhugiri, Stephan Pleschka, John Ziebuhr, Roland K Hartmann, Arnold Grünweller
Coronaviruses (CoV) and picornaviruses are plus-strand RNA viruses that use 5' cap-dependent and cap-independent strategies, respectively, for viral mRNA translation initiation. Here, we analyzed the effects of the plant compound silvestrol, a specific inhibitor of the DEAD-box RNA helicase eIF4A, on viral translation using a dual luciferase assay and virus-infected primary cells. Silvestrol was recently shown to have potent antiviral activity in Ebola virus-infected human macrophages. We found that silvestrol is also a potent and non-toxic inhibitor of cap-dependent viral mRNA translation in CoV-infected human embryonic lung fibroblast (MRC-5) cells...
December 16, 2017: Antiviral Research
https://www.readbyqxmd.com/read/29228324/usp9x-controls-translation-efficiency-via-deubiquitination-of-eukaryotic-translation-initiation-factor-4a1
#8
Zengxia Li, Zhao Cheng, Chaerkady Raghothama, Zhaomeng Cui, Kaiyu Liu, Xiaojing Li, Chenxiao Jiang, Wei Jiang, Minjia Tan, Xiaohua Ni, Akhilesh Pandey, Jun O Liu, Yongjun Dang
Controlling translation initiation is an efficient way to regulate gene expression at the post-transcriptional level. However, current knowledge regarding regulatory proteins and their modes of controlling translation initiation is still limited. In this study, we employed tandem affinity purification and mass spectrometry to screen for unknown proteins associated with the translation initiation machinery. Ubiquitin specific peptidase 9, X-linked (USP9X), was identified as a novel binding partner, that interacts with the eukaryotic translation initiation factor 4B (eIF4B) in a mRNA-independent manner...
December 8, 2017: Nucleic Acids Research
https://www.readbyqxmd.com/read/29222490/ran-translation-at-c9orf72-associated-repeat-expansions-is-selectively-enhanced-by-the-integrated-stress-response
#9
Katelyn M Green, M Rebecca Glineburg, Michael G Kearse, Brittany N Flores, Alexander E Linsalata, Stephen J Fedak, Aaron C Goldstrohm, Sami J Barmada, Peter K Todd
Repeat-associated non-AUG (RAN) translation allows for unconventional initiation at disease-causing repeat expansions. As RAN translation contributes to pathogenesis in multiple neurodegenerative disorders, determining its mechanistic underpinnings may inform therapeutic development. Here we analyze RAN translation at G4C2 repeat expansions that cause C9orf72-associated amyotrophic lateral sclerosis and frontotemporal dementia (C9RAN) and at CGG repeats that cause fragile X-associated tremor/ataxia syndrome...
December 8, 2017: Nature Communications
https://www.readbyqxmd.com/read/29203851/dynamic-landscape-of-the-local-translation-at-activated-synapses
#10
T M Khlebodarova, V V Kogai, E A Trifonova, V A Likhoshvai
The mammalian target of rapamycin (mTOR) signaling pathway is the central regulator of cap-dependent translation at the synapse. Disturbances in mTOR pathway have been associated with several neurological diseases, such as autism and epilepsy. RNA-binding protein FMRP, a negative regulator of translation initiation, is one of the key components of the local translation system. Activation and inactivation of FMRP occurs via phosphorylation by S6 kinase and dephosphorylation by PP2A phosphatase, respectively...
December 5, 2017: Molecular Psychiatry
https://www.readbyqxmd.com/read/29166596/the-gcn2-atf4-signaling-pathway-induces-4e-bp-to-bias-translation-and-boost-antimicrobial-peptide-synthesis-in-response-to-bacterial-infection
#11
Deepika Vasudevan, Nicholas K Clark, Jessica Sam, Victoria C Cotham, Beatrix Ueberheide, Michael T Marr, Hyung Don Ryoo
Bacterial infection often leads to suppression of mRNA translation, but hosts are nonetheless able to express immune response genes through as yet unknown mechanisms. Here, we use a Drosophila model to demonstrate that antimicrobial peptide (AMP) production during infection is paradoxically stimulated by the inhibitor of cap-dependent translation, 4E-BP (eIF4E-binding protein; encoded by the Thor gene). We found that 4E-BP is induced upon infection with pathogenic bacteria by the stress-response transcription factor ATF4 and its upstream kinase, GCN2...
November 21, 2017: Cell Reports
https://www.readbyqxmd.com/read/29165424/functional-5-utr-mrna-structures-in-eukaryotic-translation-regulation-and-how-to-find-them
#12
REVIEW
Kathrin Leppek, Rhiju Das, Maria Barna
RNA molecules can fold into intricate shapes that can provide an additional layer of control of gene expression beyond that of their sequence. In this Review, we discuss the current mechanistic understanding of structures in 5' untranslated regions (UTRs) of eukaryotic mRNAs and the emerging methodologies used to explore them. These structures may regulate cap-dependent translation initiation through helicase-mediated remodelling of RNA structures and higher-order RNA interactions, as well as cap-independent translation initiation through internal ribosome entry sites (IRESs), mRNA modifications and other specialized translation pathways...
November 22, 2017: Nature Reviews. Molecular Cell Biology
https://www.readbyqxmd.com/read/29116477/4egi-1-represses-cap-dependent-translation-and-regulates-genome-wide-translation-in-malignant-pleural-mesothelioma
#13
Arpita De, Blake A Jacobson, Mark S Peterson, Joe Jay-Dixon, Marian G Kratzke, Ahad A Sadiq, Manish R Patel, Robert A Kratzke
Deregulation of cap-dependent translation has been implicated in the malignant transformation of numerous human tissues. 4EGI-1, a novel small-molecule inhibitor of cap-dependent translation, disrupts formation of the eukaryotic initiation factor 4F (eIF4F) complex. The effects of 4EGI-1-mediated inhibition of translation initiation in malignant pleural mesothelioma (MPM) were examined. 4EGI-1 preferentially inhibited cell viability and induced apoptosis in MPM cells compared to normal mesothelial (LP9) cells...
November 8, 2017: Investigational New Drugs
https://www.readbyqxmd.com/read/29112379/high-throughput-chemical-probing-of-full-length-protein-protein-interactions
#14
James M Song, Arya Menon, Dylan C Mitchell, Oleta T Johnson, Amanda L Garner
Human biology is regulated by a complex network of protein-protein interactions (PPIs), and disruption of this network has been implicated in many diseases. However, the targeting of PPIs remains a challenging area for chemical probe and drug discovery. Although many methodologies have been put forth to facilitate these efforts, new technologies are still needed. Current biochemical assays for PPIs are typically limited to motif-domain and domain-domain interactions, and assays that will enable the screening of full-length protein systems, which are more biologically relevant, are sparse...
November 14, 2017: ACS Combinatorial Science
https://www.readbyqxmd.com/read/29107537/base-resolution-mapping-reveals-distinct-m-1-a-methylome-in-nuclear-and-mitochondrial-encoded-transcripts
#15
Xiaoyu Li, Xushen Xiong, Meiling Zhang, Kun Wang, Ying Chen, Jun Zhou, Yuanhui Mao, Jia Lv, Danyang Yi, Xiao-Wei Chen, Chu Wang, Shu-Bing Qian, Chengqi Yi
Gene expression can be post-transcriptionally regulated via dynamic and reversible RNA modifications. N(1)-methyladenosine (m(1)A) is a recently identified mRNA modification; however, little is known about its precise location and biogenesis. Here, we develop a base-resolution m(1)A profiling method, based on m(1)A-induced misincorporation during reverse transcription, and report distinct classes of m(1)A methylome in the human transcriptome. m(1)A in 5' UTR, particularly those at the mRNA cap, associate with increased translation efficiency...
October 25, 2017: Molecular Cell
https://www.readbyqxmd.com/read/29107534/m-6-a-facilitates-eif4f-independent-mrna-translation
#16
Ryan A Coots, Xiao-Min Liu, Yuanhui Mao, Leiming Dong, Jun Zhou, Ji Wan, Xingqian Zhang, Shu-Bing Qian
In eukaryotic cells, protein synthesis typically begins with the binding of eIF4F to the 7-methylguanylate (m(7)G) cap found on the 5' end of the majority of mRNAs. Surprisingly, overall translational output remains robust under eIF4F inhibition. The broad spectrum of eIF4F-resistant translatomes is incompatible with cap-independent translation mediated by internal ribosome entry sites (IRESs). Here, we report that N(6)-methyladenosine (m(6)A) facilitates mRNA translation that is resistant to eIF4F inactivation...
October 23, 2017: Molecular Cell
https://www.readbyqxmd.com/read/29107182/identification-of-the-internal-ribosome-entry-sites-ires-of-prion-protein-gene
#17
Xiao-Nuan Luo, Qin-Qin Song, Jie Yu, Juan Song, Xin-Ling Wang, Dong Xia, Peng Sun, Jun Han
Many studies demonstrated that there are several type bands of prion protein in cells. However, the formation of different prion protein bands is elusive. After several low molecular weight bands of prion protein appeared in SMB-S15 cells infected with scrapie agent Chandler, we think that IRES-dependent translation mechanism induced by prion is involved in the formation of prion protein bands. Then we designed a series of pPrP-GFP fusing plasmids and bicistronic plasmids to identify the IRES sites of prion protein gene and found 3 IRES sites inside of PrP mRNA...
October 26, 2017: International Journal of Biochemistry & Cell Biology
https://www.readbyqxmd.com/read/29093101/vp1-and-vp3-are-required-and-sufficient-for-translation-initiation-of-uncapped-ibdv-genomic-dsrna
#18
Chengjin Ye, Yu Wang, Enli Zhang, Xinpeng Han, Zhaoli Yu, Hebin Liu
Infectious bursal disease virus (IBDV) is a bi-segmented double-strand RNA (dsRNA) virus of the Birnaviridae family. While IBDV genomic dsRNA lacks a 5' cap, the means by which the uncapped IBDV genomic RNA is translated effectively is unknown. In this study, we describe a cap-independent pathway of translation initiation of IBDV uncapped RNA that relies on VP1 and VP3. We show that neither purified IBDV genomic dsRNA nor the uncapped viral plus-sense RNA transcripts was directly translated and rescued into infectious viruses in host cells...
November 1, 2017: Journal of Virology
https://www.readbyqxmd.com/read/29028794/condensin-ii-and-gait-complexes-cooperate-to-restrict-line-1-retrotransposition-in-epithelial-cells
#19
Jacqueline R Ward, Kommireddy Vasu, Emily Deutschman, Dalia Halawani, Peter A Larson, Dongmei Zhang, Belinda Willard, Paul L Fox, John V Moran, Michelle S Longworth
LINE-1 (L1) retrotransposons can mobilize (retrotranspose) within the human genome, and mutagenic de novo L1 insertions can lead to human diseases, including cancers. As a result, cells are actively engaged in preventing L1 retrotransposition. This work reveals that the human Condensin II complex restricts L1 retrotransposition in both non-transformed and transformed cell lines through inhibition of L1 transcription and translation. Condensin II subunits, CAP-D3 and CAP-H2, interact with members of the Gamma-Interferon Activated Inhibitor of Translation (GAIT) complex including the glutamyl-prolyl-tRNA synthetase (EPRS), the ribosomal protein L13a, Glyceraldehyde 3-phosphate dehydrogenase (GAPDH), and NS1 associated protein 1 (NSAP1)...
October 2017: PLoS Genetics
https://www.readbyqxmd.com/read/28982715/capturing-the-asc1p-rack1-microenvironment-at-the-head-region-of-the-40s-ribosome-with-quantitative-bioid-in-yeast
#20
Nadine Opitz, Kerstin Schmitt, Verena Hofer-Pretz, Bettina Neumann, Heike Krebber, Gerhard H Braus, Oliver Valerius
The Asc1 protein of Saccharomyces cerevisiae is a scaffold protein at the head region of ribosomal 40S that links mRNA translation to cellular signaling. In this study, proteins that co-localize with Asc1p were identified with proximity-dependent Biotin IDentification (BioID), an in vivo labeling technique described here for the first time for yeast. Biotinylated Asc1p-birA*-proximal proteins were identified and quantitatively verified against controls applying SILAC and mass spectrometry. The mRNA-binding proteins Sro9p and Gis2p appeared together with Scp160p, each providing ribosomes with nuclear transcripts...
October 5, 2017: Molecular & Cellular Proteomics: MCP
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