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Chengfei Liu, Allen C Gao
IFNγ has antitumorigenic effects; however, the findings of IFNγ in promoting the tumor cell survival and inducing adaptive immune resistance via CD4+ T-cell loss and programmed death ligand 1 (PD-L1) upregulation challenge this concept. Lo and colleagues determined that IFNγ induces epithelial-mesenchymal transition (EMT) by regulating the turnover of miRNA in prostate cancer, emphasizing the duplicitous effects of IFNγ. IFIT5, an IFN-induced tetratricopeptide repeat (IFIT) family member, was found to form a complex with the exoribonuclease-XRN1 to process miRNA maturation...
March 15, 2019: Cancer Research
Patrick D Cherry, Sally E Peach, Jay R Hesselberth
In the unfolded protein response (UPR), stress in the endoplasmic reticulum (ER) activates a large transcriptional program to increase ER folding capacity. During the budding yeast UPR, Ire1 excises an intron from the HAC1 mRNA and the exon products of cleavage are ligated, and the translated protein induces hundreds of stress-response genes. Using cells with mutations in RNA repair and decay enzymes, we show that phosphorylation of two different HAC1 splicing intermediates is required for their degradation by the 5'→3' exonuclease Xrn1 to enact opposing effects on the UPR...
March 15, 2019: ELife
Manuel Garcia-Moreno, Marko Noerenberg, Shuai Ni, Aino I Järvelin, Esther González-Almela, Caroline E Lenz, Marcel Bach-Pages, Victoria Cox, Rosario Avolio, Thomas Davis, Svenja Hester, Thibault J M Sohier, Bingnan Li, Gregory Heikel, Gracjan Michlewski, Miguel A Sanz, Luis Carrasco, Emiliano P Ricci, Vicent Pelechano, Ilan Davis, Bernd Fischer, Shabaz Mohammed, Alfredo Castello
The compendium of RNA-binding proteins (RBPs) has been greatly expanded by the development of RNA-interactome capture (RIC). However, it remained unknown if the complement of RBPs changes in response to environmental perturbations and whether these rearrangements are important. To answer these questions, we developed "comparative RIC" and applied it to cells challenged with an RNA virus called sindbis (SINV). Over 200 RBPs display differential interaction with RNA upon SINV infection. These alterations are mainly driven by the loss of cellular mRNAs and the emergence of viral RNA...
February 15, 2019: Molecular Cell
Abhishek Shetty, Thejaswini Venkatesh, Rie Tsutsumi, Padmanaban S Suresh
The aim of this study was to evaluate whether Gemin 5, Cpeb, Xrn1, and Stau1 expression in rodent ovaries and uterine tissues is dependent on gonadotropins, steroid hormones, and leptin in the superovulation and ovariectomized mouse models of menopause. Treatment of pregnant mare serum gonadotropin-primed rats with human chorionic gonadotropin (hCG) significantly induced Stau1 and Gemin 5 messenger RNA expression in rat ovaries. Gemin 5 expression in ovaries was sustained at relatively high levels at 12 h and 24 h post hCG treatment compared to Stau1, suggesting its role in follicle development, ovulation, and luteogenesis in rat ovaries...
January 28, 2019: Molecular Biology Reports
Sujatha Jagannathan, Yuko Ogata, Philip R Gafken, Stephen J Tapscott, Robert K Bradley
DUX4 is a transcription factor whose misexpression in skeletal muscle causes facioscapulohumeral muscular dystrophy (FSHD). DUX4's transcriptional activity has been extensively characterized, but the DUX4-induced proteome remains undescribed. Here, we report concurrent measurement of RNA and protein levels in DUX4-expressing cells via RNA-seq and quantitative mass spectrometry. DUX4 transcriptional targets were robustly translated, confirming the likely clinical relevance of proposed FSHD biomarkers. However, a multitude of mRNAs and proteins exhibited discordant expression changes upon DUX4 expression...
January 15, 2019: ELife
Joseph Russo, Cary T Mundell, Phillida A Charley, Carol Wilusz, Jeffrey Wilusz
Both RNA synthesis and decay must be balanced within a cell to achieve proper gene expression. Additionally, modulation of RNA decay specifically offers the cell an opportunity to rapidly reshape the transcriptome in response to specific stimuli or cues. Therefore, it is critical to understand the underlying mechanisms through which RNA decay contribute to gene expression homeostasis. Cell-free reconstitution approaches have been used successfully to reveal mechanisms associated with numerous post-transcriptional RNA processes...
December 3, 2018: Methods: a Companion to Methods in Enzymology
Wenshuang Li, David Carrasco Flores, Juliane Füßel, Jan Euteneuer, Hannes Dathe, Yong Zou, Wolfram Weisheit, Volker Wagner, Jan Petersen, Maria Mittag
Microalgae contribute significantly to carbon fixation on Earth. Global warming influences their physiology and growth rates. To understand algal short-term acclimation and adaptation to changes in ambient temperature, it is essential to identify and characterize the molecular components that sense small temperature changes, as well as the downstream signaling networks and physiological responses. Here, we used the green biflagellate alga Chlamydomonas reinhardtii as a model system to study responses to temperature...
October 9, 2018: Plant Physiology
Sarah Gilbertson, Joel D Federspiel, Ella Hartenian, Ileana M Cristea, Britt Glaunsinger
Alterations in global mRNA decay broadly impact multiple stages of gene expression, although signals that connect these processes are incompletely defined. Here, we used tandem mass tag labeling coupled with mass spectrometry to reveal that changing the mRNA decay landscape, as frequently occurs during viral infection, results in subcellular redistribution of RNA binding proteins (RBPs) in human cells. Accelerating Xrn1-dependent mRNA decay through expression of a gammaherpesviral endonuclease drove nuclear translocation of many RBPs, including poly(A) tail-associated proteins...
October 3, 2018: ELife
Andrii Slonchak, Alexander A Khromykh
The common feature of flaviviral infection is the accumulation of abundant virus-derived noncoding RNA, named flaviviral subgenomic RNA (sfRNA) in infected cells. This RNA represents a product of incomplete degradation of viral genomic RNA by the cellular 5'-3' exoribonuclease XRN1 that stalls at the conserved highly structured elements in the 3' untranslated region (UTR). This mechanism of sfRNA generation was discovered a decade ago and since then sfRNA has been a focus of intense research. The ability of flaviviruses to produce sfRNA was shown to be evolutionary conserved in all members of Flavivirus genus...
September 11, 2018: Antiviral Research
Ji-Sook Yun, Je-Hyun Yoon, Young Jun Choi, Young Jin Son, Sunghwan Kim, Liang Tong, Jeong Ho Chang
The decapping exoribonuclease DXO functions in pre-mRNA capping quality control, and shows multiple biochemical activities such as decapping, deNADding, pyrophosphohydrolase, and 5'-3' exoribonuclease activities. Previous studies revealed the molecular mechanisms of DXO based on the structures in complexes with a product, substrate mimic, cap analogue, and 3'-NADP+ . Despite several reports on the substrate-specific reaction mechanism, the inhibitory mechanism of DXO remains elusive. Here, we demonstrate that adenosine 3', 5'-bisphosphate (pAp), a known inhibitor of the 5'-3' exoribonuclease Xrn1, inhibits the nuclease activity of DXO based on the results of structural and biochemical experiments...
September 26, 2018: Biochemical and Biophysical Research Communications
Benjamin P Towler, Sarah F Newbury
The process of RNA degradation is a critical level of regulation contributing to the control of gene expression. In the last two decades a number of studies have shown the specific and targeted nature of RNA decay and its importance in maintaining homeostasis. The key players within the pathways of RNA decay are well conserved with their mutation or disruption resulting in distinct phenotypes as well as human disease. Model organisms including Drosophila melanogaster have played a substantial role in elucidating the mechanisms conferring control over RNA stability...
November 2018: Wiley Interdisciplinary Reviews. RNA
Seyed Mojtaba Ghiasi, Nicolai Krogh, Björn Tyrberg, Thomas Mandrup-Poulsen
Stress-related changes in β-cell mRNA levels result from a balance between gene transcription and mRNA decay. The regulation of RNA decay pathways has not been investigated in pancreatic β-cells. We found that no-go and nonsense-mediated RNA decay pathway components (RDPCs) and exoribonuclease complexes were expressed in INS-1 cells and human islets. Pelo, Dcp2, Dis3L2, Upf2, and Smg1/5/6/7 were upregulated by inflammatory cytokines in INS-1 cells under conditions where central β-cell mRNAs were downregulated...
October 2018: Diabetes
Yi-Shiuan Chen, Yi-Hsin Fan, Chih-Feng Tien, Andrew Yueh, Ruey-Yi Chang
Flaviviruses accumulate abundant subgenomic RNA (sfRNA) in infected cells. It has been reported that sfRNA results from stalling of host 5'-to-3' exoribonuclease XRN1 at the highly structured RNA of the 3' untranslated region (UTR). Although XRN1 digestion of a 3'-terminal 800-nt RNA could stall at a position to generate the sfRNA in vitro, we found that knocking out XRN1 had no effect on the accumulation of sfRNA in Japanese encephalitis virus (JEV) infected cells. Mutagenesis studies revealed that the stemloop II (SLII) at the 3' UTR is required for the accumulation of sfRNA...
2018: PloS One
Jens Kretschmer, Harita Rao, Philipp Hackert, Katherine E Sloan, Claudia Höbartner, Markus T Bohnsack
N 6 -methyladenosine (m6 A) modifications in RNAs play important roles in regulating many different aspects of gene expression. While m6 As can have direct effects on the structure, maturation, or translation of mRNAs, such modifications can also influence the fate of RNAs via proteins termed "readers" that specifically recognize and bind modified nucleotides. Several YTH domain-containing proteins have been identified as m6 A readers that regulate the splicing, translation, or stability of specific mRNAs...
October 2018: RNA
Sophie R Atkinson, Samuel Marguerat, Danny A Bitton, Maria Rodríguez-López, Charalampos Rallis, Jean-François Lemay, Cristina Cotobal, Michal Malecki, Pawel Smialowski, Juan Mata, Philipp Korber, François Bachand, Jürg Bähler
Long noncoding RNAs (lncRNAs), which are longer than 200 nucleotides but often unstable, contribute a substantial and diverse portion to pervasive noncoding transcriptomes. Most lncRNAs are poorly annotated and understood, although several play important roles in gene regulation and diseases. Here we systematically uncover and analyze lncRNAs in Schizosaccharomyces pombe. Based on RNA-seq data from twelve RNA-processing mutants and nine physiological conditions, we identify 5775 novel lncRNAs, nearly 4× the previously annotated lncRNAs...
September 2018: RNA
Yalena Amador-Cañizares, Annie Bernier, Joyce A Wilson, Selena M Sagan
Hepatitis C virus (HCV) recruits two molecules of the liver-specific microRNA-122 (miR-122) to the 5' end of its genome. This interaction promotes viral RNA accumulation, but the precise mechanism(s) remain incompletely understood. Previous studies suggest that miR-122 is able to protect the HCV genome from 5' exonucleases (Xrn1/2), but this protection is not sufficient to account for the effect of miR-122 on HCV RNA accumulation. Thus, we investigated whether miR-122 was also able to protect the viral genome from innate sensors of RNA or cellular pyrophosphatases...
June 1, 2018: Nucleic Acids Research
Alyssa Flobinus, Nicolas Chevigny, Phillida A Charley, Tanja Seissler, Elodie Klein, Claudine Bleykasten-Grosshans, Claudio Ratti, Salah Bouzoubaa, Jeffrey Wilusz, David Gilmer
The RNA3 species of the beet necrotic yellow vein virus (BNYVV), a multipartite positive-stranded RNA phytovirus, contains the 'core' nucleotide sequence required for its systemic movement in Beta macrocarpa . Within this 'core' sequence resides a conserved "coremin" motif of 20 nucleotides that is absolutely essential for long-distance movement. RNA3 undergoes processing steps to yield a noncoding RNA3 (ncRNA3) possessing "coremin" at its 5' end, a mandatory element for ncRNA3 accumulation...
March 19, 2018: Viruses
Joséphine Zangari, Marius Ilie, Florian Rouaud, Laurie Signetti, Mickaël Ohanna, Robin Didier, Barnabé Roméo, Dana Goldoni, Nicolas Nottet, Cathy Staedel, Jocelyn Gal, Bernard Mari, Baharia Mograbi, Paul Hofman, Patrick Brest
No abstract text is available yet for this article.
April 20, 2018: Nucleic Acids Research
Saijo Thomas, Jiyoti Verma, Megan Woolfit, Scott L O'Neill
Wolbachia is currently being developed as a novel tool to block the transmission of dengue viruses (DENV) by Aedes aegypti. A number of mechanisms have been proposed to explain the DENV-blocking phenotype in mosquitoes, including competition for fatty acids like cholesterol, manipulation of host miRNAs and upregulation of innate immune pathways in the mosquito. We examined the various stages in the DENV infection process to better understand the mechanism of Wolbachia-mediated virus blocking (WMVB). Our results suggest that infection with Wolbachia does not inhibit DENV binding or cell entry, but reduces virus replication...
March 2018: PLoS Pathogens
Elizabeth Delorme-Axford, Emma Abernathy, Nicholas J Lennemann, Amélie Bernard, Aileen Ariosa, Carolyn B Coyne, Karla Kirkegaard, Daniel J Klionsky
Macroautophagy/autophagy is a conserved catabolic process that promotes survival during stress. Autophagic dysfunction is associated with pathologies such as cancer and neurodegenerative diseases. Thus, autophagy must be strictly modulated at multiple levels (transcriptional, post-transcriptional, translational and post-translational) to prevent deregulation. Relatively little is known about the post-transcriptional control of autophagy. Here we report that the exoribonuclease Xrn1/XRN1 functions as a negative autophagy factor in the yeast Saccharomyces cerevisiae and in mammalian cells...
2018: Autophagy
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