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ribosome stall

Koreaki Ito, Hiroyuki Mori, Shinobu Chiba
Protein localization machinery supports cell survival and physiology, suggesting the potential importance of its expression regulation. Here, we summarize a remarkable scheme of regulation, which allows real-time feedback regulation of the machinery expression. A class of regulatory nascent polypeptides, called monitoring substrates, undergoes force-sensitive translation arrest. The resulting ribosome stalling on the mRNA then affects mRNA folding to expose the ribosome-binding site of the downstream target gene and upregulate its translation...
June 1, 2018: FEMS Microbiology Letters
Bin Liu, Chunlai Chen
Even though elongation factor 4 (EF4) is the third most conserved protein in bacteria, its physiological functions remain largely unknown and its proposed molecular mechanisms are conflicting among previous studies. In the present study we show that growth of an Escherichia coli strain is more susceptible to tetracycline than its EF4 knockout strain. In consistence with previous studies, our results suggested that EF4 affects ribosome biogenesis when tetracycline is present. Through ribosome profiling analysis, we discovered that EF4 causes 1-nucleotide shifting of ribosomal footprints on mRNA when cells have been exposed to tetracycline...
May 21, 2018: Antimicrobial Agents and Chemotherapy
Zhong-Ke Jiang, Li Tuo, Da-Lin Huang, Ilya A Osterman, Anton P Tyurin, Shao-Wei Liu, Dmitry A Lukyanov, Petr V Sergiev, Olga A Dontsova, Vladimir A Korshun, Fei-Na Li, Cheng-Hang Sun
Endophytic actinobacteria are one of the important pharmaceutical resources and well known for producing different types of bioactive substances. Nevertheless, detection of the novelty, diversity, and bioactivity on endophytic actinobacteria isolated from mangrove plants are scarce. In this study, five different mangrove plants, Avicennia marina, Aegiceras corniculatum, Kandelia obovota, Bruguiera gymnorrhiza , and Thespesia populnea , were collected from Beilun Estuary National Nature Reserve in Guangxi Zhuang Autonomous Region, China...
2018: Frontiers in Microbiology
Anthony P Schuller, Rachel Green
During protein synthesis, ribosomes encounter many roadblocks, the outcomes of which are largely determined by substrate availability, amino acid features and reaction kinetics. Prolonged ribosome stalling is likely to be resolved by ribosome rescue or quality control pathways, whereas shorter stalling is likely to be resolved by ongoing productive translation. How ribosome function is affected by such hindrances can therefore have a profound impact on the translational output (yield) of a particular mRNA. In this Review, we focus on these roadblocks and the resumption of normal translation elongation rather than on alternative fates wherein the stalled ribosome triggers degradation of the mRNA and the incomplete protein product...
May 14, 2018: Nature Reviews. Molecular Cell Biology
Stephen DiGiuseppe, Madeline G Rollins, Elizabeth T Bartom, Derek Walsh
Post-translational modification of ribosomal subunit proteins (RPs) is emerging as an important means of regulating gene expression. Recently, regulatory ubiquitination of small RPs RPS10 and RPS20 by the ubiquitin ligase ZNF598 was found to function in ribosome sensing and stalling on internally polyadenylated mRNAs during ribosome quality control (RQC). Here, we reveal that ZNF598 and RPS10 negatively regulate interferon-stimulated gene (ISG) expression in primary cells, depletion of which induced ISG expression and a broad antiviral state...
May 1, 2018: Cell Reports
Mareike Bütepage, Christian Preisinger, Alexander von Kriegsheim, Anja Scheufen, Eva Lausberg, Jinyu Li, Ferdinand Kappes, Regina Feederle, Sabrina Ernst, Laura Eckei, Sarah Krieg, Gerhard Müller-Newen, Giulia Rossetti, Karla L H Feijs, Patricia Verheugd, Bernhard Lüscher
Macrodomains are conserved protein folds associated with ADP-ribose binding and turnover. ADP-ribosylation is a posttranslational modification catalyzed primarily by ARTD (aka PARP) enzymes in cells. ARTDs transfer either single or multiple ADP-ribose units to substrates, resulting in mono- or poly-ADP-ribosylation. TARG1/C6orf130 is a macrodomain protein that hydrolyzes mono-ADP-ribosylation and interacts with poly-ADP-ribose chains. Interactome analyses revealed that TARG1 binds strongly to ribosomes and proteins associated with rRNA processing and ribosomal assembly factors...
April 30, 2018: Scientific Reports
Yusuke Umegaki, Antonio Martinéz Brotons, Yui Nakanishi, Zhongyue Luo, Hanlu Zhang, Azad Bonni, Yoshiho Ikeuchi
The mTOR signaling pathway regulates protein synthesis and diverse aspects of neuronal morphology that are important for brain development and function. To identify proteins controlled translationally by mTOR signaling, we performed ribosome profiling analyses in mouse cortical neurons and embryonic stem cells upon acute mTOR inhibition. Among proteins whose translation was significantly affected by mTOR inhibition selectively in neurons, we identified the cytoskeletal regulator protein Palladin, which is localized within the cell body and axons in hippocampal neurons...
April 30, 2018: Journal of Neuroscience: the Official Journal of the Society for Neuroscience
Scot P Ouellette, Parker R Messerli, Nicholas A Wood, Heather Hajovsky
As an obligate intracellular, developmentally regulated bacterium, Chlamydia is sensitive to amino acid fluctuations within its host cell. When human epithelial cells are treated with the cytokine interferon-γ (IFNγ), the tryptophan (trp)-degrading enzyme, indoleamine-2,3-dioxygenase, is induced. Chlamydiae within such cells are starved for trp and enter a state of so-called persistence. Chlamydia lacks the stringent response used by many eubacteria to respond to this stress. Unusually, chlamydial transcription is globally elevated during trp starvation with transcripts for trp-codon containing genes disproportionately increased...
April 30, 2018: Infection and Immunity
Hoang Linh Nguyen, Dang Lan Pham, Edward P O'Brien, Mai Suan Li
The antibiotic activity of erythromycin, which reversibly binds to a site within the bacterial ribosome exit tunnel, against many gram positive microorganisms indicates that it effectively inhibits the production of proteins. Similar to other macrolides, the activity of erythromycin is far from universal, as some peptides can bypass the macrolide-obstructed exit tunnel and become partially or fully synthesized. It is unclear why, at the molecular level, some proteins can be synthesized while others cannot...
April 24, 2018: Scientific Reports
Ivaylo P Ivanov, Byung-Sik Shin, Gary Loughran, Ioanna Tzani, Sara K Young-Baird, Chune Cao, John F Atkins, Thomas E Dever
Translation initiation is typically restricted to AUG codons, and scanning eukaryotic ribosomes inefficiently recognize near-cognate codons. We show that queuing of scanning ribosomes behind a paused elongating ribosome promotes initiation at upstream weak start sites. Ribosomal profiling reveals polyamine-dependent pausing of elongating ribosomes on a conserved Pro-Pro-Trp (PPW) motif in an inhibitory non-AUG-initiated upstream conserved coding region (uCC) of the antizyme inhibitor 1 (AZIN1) mRNA, encoding a regulator of cellular polyamine synthesis...
April 19, 2018: Molecular Cell
Nathanael G Lintner, Kim F McClure, Donna Petersen, Allyn T Londregan, David W Piotrowski, Liuqing Wei, Jun Xiao, Michael Bolt, Paula M Loria, Bruce Maguire, Kieran F Geoghegan, Austin Huang, Tim Rolph, Spiros Liras, Jennifer A Doudna, Robert G Dullea, Jamie H D Cate
[This corrects the article DOI: 10.1371/journal.pbio.2001882.].
April 2018: PLoS Biology
Kifayathullah Liakath-Ali, Eric W Mills, Inês Sequeira, Beate M Lichtenberger, Angela Oliveira Pisco, Kalle H Sipilä, Ajay Mishra, Harunori Yoshikawa, Colin Chih-Chien Wu, Tony Ly, Angus I Lamond, Ibrahim M Adham, Rachel Green, Fiona M Watt
Ribosome-associated mRNA quality control mechanisms ensure the fidelity of protein translation1,2 . Although these mechanisms have been extensively studied in yeast, little is known about their role in mammalian tissues, despite emerging evidence that stem cell fate is controlled by translational mechanisms3,4 . One evolutionarily conserved component of the quality control machinery, Dom34 (in higher eukaryotes known as Pelota (Pelo)), rescues stalled ribosomes 5 . Here we show that Pelo is required for mammalian epidermal homeostasis...
April 11, 2018: Nature
Nathan Zuzow, Arit Ghosh, Marilyn Leonard, Jeffrey Liao, Bing Yang, Eric J Bennett
Previous genetic and biochemical studies from Saccharomyces cerevisiae have identified a critical ribosome-associated quality control complex (RQC) that facilitates resolution of stalled ribosomal complexes. While components of the mammalian RQC have been examined in vitro, a systematic characterization of RQC protein interactions in mammalian cells has yet to be described. Here we utilize both proximity-labeling proteomic approaches, BioID and APEX, and traditional affinity-based strategies to both identify interacting proteins of mammalian RQC members and putative substrates for the RQC resident E3 ligase, Ltn1...
May 15, 2018: Molecular Biology of the Cell
Widler Casy, Austin R Prater, Peter V Cornish
During translation, the small subunit of the ribosome rotates with respect to the large subunit primarily between two states as mRNA is being translated into a protein. At the termination of bacterial translation, class I release factors (RFs) bind to a stop codon in the A-site and catalyze the release of the peptide chain from the ribosome. Periodically, mRNA is truncated prematurely, and the translating ribosome stalls at the end of the mRNA forming a nonstop complex requiring one of several ribosome rescue factors to intervene...
April 3, 2018: Biochemistry
René Toribio, Irene Díaz-López, Jasminka Boskovic, Iván Ventoso
The topology and dynamics of the scanning ribosomal 43S pre-initiation complex (PIC) bound to mRNA and initiation factors (eIFs) are probably the least understood aspects of translation initiation in eukaryotes. Recently, we described a trapping mechanism in alphavirus that stalls the PIC during scanning of viral mRNA. Using this model, we were able to snapshot for the first time the eIF4A helicase bound to mRNA in a 48S initiation complex assembled in vitro. This interaction was only detected in the presence of the natural stem loop structure (DLP) located downstream from the AUG in viral mRNA that promoted stalling of the PIC, suggesting that DLP stability was enough to jam the helicase activity of eIF4A in a fraction of assembled 48S complexes...
February 5, 2018: Nucleic Acids Research
Fei Qi, Magdalena Motz, Kirsten Jung, Jürgen Lassak, Dmitrij Frishman
Translation of consecutive prolines causes ribosome stalling, which is alleviated but cannot be fully compensated by the elongation factor P. However, the presence of polyproline motifs in about one third of the E. coli proteins underlines their potential functional importance, which remains largely unexplored. We conducted an evolutionary analysis of polyproline motifs in the proteomes of 43 E. coli strains and found evidence of evolutionary selection against translational stalling, which is especially pronounced in proteins with high translational efficiency...
February 2018: PLoS Computational Biology
Brittany D Bennett, Kaitlyn E Redford, Jeffrey A Gralnick
Shewanella oneidensis strain MR-1 is a versatile bacterium capable of respiring extracellular, insoluble ferric oxide minerals under anaerobic conditions. The respiration of iron minerals results in the production of soluble ferrous ions, which at high concentrations are toxic to living organisms. It is not fully understood how Fe2+ is toxic to cells anaerobically, nor is it fully understood how S. oneidensis is able to resist high levels of Fe2+ Here we describe the results of a transposon mutant screen and subsequent deletion of the genes clpX and clpP in S...
April 15, 2018: Journal of Bacteriology
Misaki Ishizuka, Yu Imai, Keiichiro Mukai, Kazuma Shimono, Ryoko Hamauzu, Kozo Ochi, Takeshi Hosaka
Lincomycin forms cross-links within the peptidyl transferase loop region of the 23S ribosomal RNA (rRNA) of the 50S subunit of the bacterial ribosome, which is the site of peptide bond formation, thereby inhibiting protein synthesis. We have previously reported that lincomycin at concentrations below the minimum inhibitory concentration potentiates the production of secondary metabolites in actinomycete strains, suggesting that activation of these strains by utilizing the dose-dependent response of lincomycin could be used to effectively induce the production of cryptic secondary metabolites...
January 25, 2018: Antonie Van Leeuwenhoek
Raphael J Morscher, Gregory S Ducker, Sophia Hsin-Jung Li, Johannes A Mayer, Zemer Gitai, Wolfgang Sperl, Joshua D Rabinowitz
Folates enable the activation and transfer of one-carbon units for the biosynthesis of purines, thymidine and methionine. Antifolates are important immunosuppressive and anticancer agents. In proliferating lymphocytes and human cancers, mitochondrial folate enzymes are particularly strongly upregulated. This in part reflects the need for mitochondria to generate one-carbon units and export them to the cytosol for anabolic metabolism. The full range of uses of folate-bound one-carbon units in the mitochondrial compartment itself, however, has not been thoroughly explored...
February 1, 2018: Nature
Xiao P Peng, Shelly Lim, Shibai Li, Lisette Marjavaara, Andrei Chabes, Xiaolan Zhao
Smc5/6, a member of the conserved SMC family of complexes, is essential for growth in most organisms. Its exact functions in a mitotic cell cycle are controversial, as chronic Smc5/6 loss-of-function alleles produce varying phenotypes. To circumvent this issue, we acutely depleted Smc5/6 in budding yeast and determined the first cell cycle consequences of Smc5/6 removal. We found a striking primary defect in replication of the ribosomal DNA (rDNA) array. Each rDNA repeat contains a programmed replication fork barrier (RFB) established by the Fob1 protein...
January 2018: PLoS Genetics
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