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Molecular Cell

Jianhua Xiong, Hiroyuki Kawagishi, Ye Yan, Jie Liu, Quinn S Wells, Lia R Edmunds, Maria M Fergusson, Zu-Xi Yu, Ilsa I Rovira, Evan L Brittain, Michael J Wolfgang, Michael J Jurczak, Joshua P Fessel, Toren Finkel
Endothelial-to-mesenchymal transition (EndoMT) is a cellular process often initiated by the transforming growth factor β (TGF-β) family of ligands. Although required for normal heart valve development, deregulated EndoMT is linked to a wide range of pathological conditions. Here, we demonstrate that endothelial fatty acid oxidation (FAO) is a critical in vitro and in vivo regulator of EndoMT. We further show that this FAO-dependent metabolic regulation of EndoMT occurs through alterations in intracellular acetyl-CoA levels...
February 7, 2018: Molecular Cell
Jun Zhou, Ji Wan, Xin Erica Shu, Yuanhui Mao, Xiao-Min Liu, Xin Yuan, Xingqian Zhang, Martin E Hess, Jens C Brüning, Shu-Bing Qian
The integrated stress response (ISR) facilitates cellular adaptation to stress conditions via the common target eIF2α. During ISR, the selective translation of stress-related mRNAs often relies on alternative mechanisms, such as leaky scanning or reinitiation, but the underlying mechanism remains incompletely understood. Here we report that, in response to amino acid starvation, the reinitiation of ATF4 is not only governed by the eIF2α signaling pathway, but is also subjected to regulation by mRNA methylation in the form of N6-methyladenosine (m6A)...
February 1, 2018: Molecular Cell
Nicolas G Bologna, Raphael Iselin, Luciano A Abriata, Alexis Sarazin, Nathan Pumplin, Florence Jay, Thomas Grentzinger, Matteo Dal Peraro, Olivier Voinnet
Unlike in metazoans, plant microRNAs (miRNAs) undergo stepwise nuclear maturation before engaging cytosolic, sequence-complementary transcripts in association with the silencing effector protein ARGONAUTE1 (AGO1). Since their discovery, how and under which form plant miRNAs translocate to the cytosol has remained unclear, as has their sub-cellular AGO1 loading site(s). Here, we show that the N termini of all plant AGO1s contain a nuclear-localization (NLS) and nuclear-export signal (NES) that, in Arabidopsis thaliana (At), enables AtAGO1 nucleo-cytosolic shuttling in a Leptomycin-B-inhibited manner, diagnostic of CRM1(EXPO1)/NES-dependent nuclear export...
January 31, 2018: Molecular Cell
Anthony C Chiu, Hiroshi I Suzuki, Xuebing Wu, Dig B Mahat, Andrea J Kriz, Phillip A Sharp
Regulation of RNA polymerase II (Pol II) elongation is a critical step in gene regulation. Here, we report that U1 snRNP recognition and transcription pausing at stable nucleosomes are linked through premature polyadenylation signal (PAS) termination. By generating RNA exosome conditional deletion mouse embryonic stem cells, we identified a large class of polyadenylated short transcripts in the sense direction destabilized by the RNA exosome. These PAS termination events are enriched at the first few stable nucleosomes flanking CpG islands and suppressed by U1 snRNP...
January 31, 2018: Molecular Cell
Cindy Meyer, Aitor Garzia, Michael Mazzola, Stefanie Gerstberger, Henrik Molina, Thomas Tuschl
TIA1 and TIAL1 encode a family of U-rich element mRNA-binding proteins ubiquitously expressed and conserved in metazoans. Using PAR-CLIP, we determined that both proteins bind target sites with identical specificity in 3' UTRs and introns proximal to 5' as well as 3' splice sites. Double knockout (DKO) of TIA1 and TIAL1 increased target mRNA abundance proportional to the number of binding sites and also caused accumulation of aberrantly spliced mRNAs, most of which are subject to nonsense-mediated decay. Loss of PRKRA by mis-splicing triggered the activation of the double-stranded RNA (dsRNA)-activated protein kinase EIF2AK2/PKR and stress granule formation...
January 26, 2018: Molecular Cell
Alexander Harms, Ditlev Egeskov Brodersen, Namiko Mitarai, Kenn Gerdes
Bacterial toxin-antitoxin (TA) modules are abundant genetic elements that encode a toxin protein capable of inhibiting cell growth and an antitoxin that counteracts the toxin. The majority of toxins are enzymes that interfere with translation or DNA replication, but a wide variety of molecular activities and cellular targets have been described. Antitoxins are proteins or RNAs that often control their cognate toxins through direct interactions and, in conjunction with other signaling elements, through transcriptional and translational regulation of TA module expression...
January 21, 2018: Molecular Cell
Veronica H Ryan, Gregory L Dignon, Gül H Zerze, Charlene V Chabata, Rute Silva, Alexander E Conicella, Joshua Amaya, Kathleen A Burke, Jeetain Mittal, Nicolas L Fawzi
hnRNPA2, a component of RNA-processing membraneless organelles, forms inclusions when mutated in a syndrome characterized by the degeneration of neurons (bearing features of amyotrophic lateral sclerosis [ALS] and frontotemporal dementia), muscle, and bone. Here we provide a unified structural view of hnRNPA2 self-assembly, aggregation, and interaction and the distinct effects of small chemical changes-disease mutations and arginine methylation-on these assemblies. The hnRNPA2 low-complexity (LC) domain is compact and intrinsically disordered as a monomer, retaining predominant disorder in a liquid-liquid phase-separated form...
January 17, 2018: Molecular Cell
Jens Hör, Stanislaw A Gorski, Jörg Vogel
Bacteria are an exceedingly diverse group of organisms whose molecular exploration is experiencing a renaissance. While the classical view of bacterial gene expression was relatively simple, the emerging view is more complex, encompassing extensive post-transcriptional control involving riboswitches, RNA thermometers, and regulatory small RNAs (sRNAs) associated with the RNA-binding proteins CsrA, Hfq, and ProQ, as well as CRISPR/Cas systems that are programmed by RNAs. Moreover, increasing interest in members of the human microbiota and environmental microbial communities has highlighted the importance of understudied bacterial species with largely unknown transcriptome structures and RNA-based control mechanisms...
January 16, 2018: Molecular Cell
Divya Seth, Douglas T Hess, Alfred Hausladen, Liwen Wang, Ya-Juan Wang, Jonathan S Stamler
S-nitrosylation, the oxidative modification of Cys residues by nitric oxide (NO) to form S-nitrosothiols (SNOs), modifies all main classes of proteins and provides a fundamental redox-based cellular signaling mechanism. However, in contrast to other post-translational protein modifications, S-nitrosylation is generally considered to be non-enzymatic, involving multiple chemical routes. We report here that endogenous protein S-nitrosylation in the model organism E. coli depends principally upon the enzymatic activity of the hybrid cluster protein Hcp, employing NO produced by nitrate reductase...
January 16, 2018: Molecular Cell
Jinlong Wang, Lauren E Grubb, Jiayu Wang, Xiangxiu Liang, Lin Li, Chulei Gao, Miaomiao Ma, Feng Feng, Meng Li, Lei Li, Xiaojuan Zhang, Feifei Yu, Qi Xie, She Chen, Cyril Zipfel, Jacqueline Monaghan, Jian-Min Zhou
Plant pattern recognition receptors (PRRs) perceive microbial and endogenous molecular patterns to activate immune signaling. The cytoplasmic kinase BIK1 acts downstream of multiple PRRs as a rate-limiting component, whose phosphorylation and accumulation are central to immune signal propagation. Previous work identified the calcium-dependent protein kinase CPK28 and heterotrimeric G proteins as negative and positive regulators of BIK1 accumulation, respectively. However, mechanisms underlying this regulation remain unknown...
January 15, 2018: Molecular Cell
Kathryn Wolhuter, Harry J Whitwell, Christopher H Switzer, Joseph R Burgoyne, John F Timms, Philip Eaton
S-nitrosation, commonly referred to as S-nitrosylation, is widely regarded as a ubiquitous, stable post-translational modification that directly regulates many proteins. Such a widespread role would appear to be incompatible with the inherent lability of the S-nitroso bond, especially its propensity to rapidly react with thiols to generate disulfide bonds. As anticipated, we observed robust and widespread protein S-nitrosation after exposing cells to nitrosocysteine or lipopolysaccharide. Proteins detected using the ascorbate-dependent biotin switch method are typically interpreted to be directly regulated by S-nitrosation...
January 12, 2018: Molecular Cell
Shinichi Machida, Yoshimasa Takizawa, Masakazu Ishimaru, Yukihiko Sugita, Satoshi Sekine, Jun-Ichi Nakayama, Matthias Wolf, Hitoshi Kurumizaka
Heterochromatin plays important roles in transcriptional silencing and genome maintenance by the formation of condensed chromatin structures, which determine the epigenetic status of eukaryotic cells. The trimethylation of histone H3 lysine 9 (H3K9me3), a target of heterochromatin protein 1 (HP1), is a hallmark of heterochromatin formation. However, the mechanism by which HP1 folds chromatin-containing H3K9me3 into a higher-order structure has not been elucidated. Here we report the three-dimensional structure of the H3K9me3-containing dinucleosomes complexed with human HP1α, HP1β, and HP1γ, determined by cryogenic electron microscopy with a Volta phase plate...
January 10, 2018: Molecular Cell
Qiang Zhang, Hai Huang, Qing Lu, Roland Wu, Chan-I Chung, Shao-Qing Zhang, Joaquim Torra, Antonino Schepis, Shaun R Coughlin, Thomas B Kornberg, Xiaokun Shu
Visualizing dynamics of kinase activity in living animals is essential for mechanistic understanding of cell and developmental biology. We describe GFP-based kinase reporters that phase-separate upon kinase activation via multivalent protein-protein interactions, forming intensively fluorescent droplets. Called SPARK (separation of phases-based activity reporter of kinase), these reporters have large dynamic range (fluorescence change), high brightness, fast kinetics, and are reversible. The SPARK-based protein kinase A (PKA) reporter reveals oscillatory dynamics of PKA activities upon G protein-coupled receptor activation...
January 3, 2018: Molecular Cell
Thomas Kruse, Nadine Biedenkopf, Emil Peter Thrane Hertz, Erik Dietzel, Gertrud Stalmann, Blanca López-Méndez, Norman E Davey, Jakob Nilsson, Stephan Becker
Transcription of the Ebola virus genome depends on the viral transcription factor VP30 in its unphosphorylated form, but the underlying molecular mechanism of VP30 dephosphorylation is unknown. Here we show that the Ebola virus nucleoprotein (NP) recruits the host PP2A-B56 protein phosphatase through a B56-binding LxxIxE motif and that this motif is essential for VP30 dephosphorylation and viral transcription. The LxxIxE motif and the binding site of VP30 in NP are in close proximity, and both binding sites are required for the dephosphorylation of VP30...
December 27, 2017: Molecular Cell
Pengcheng Wang, Yang Zhao, Zhongpeng Li, Chuan-Chih Hsu, Xue Liu, Liwen Fu, Yueh-Ju Hou, Yanyan Du, Shaojun Xie, Chunguang Zhang, Jinghui Gao, Minjie Cao, Xiaosan Huang, Yingfang Zhu, Kai Tang, Xingang Wang, W Andy Tao, Yan Xiong, Jian-Kang Zhu
As sessile organisms, plants must adapt to variations in the environment. Environmental stress triggers various responses, including growth inhibition, mediated by the plant hormone abscisic acid (ABA). The mechanisms that integrate stress responses with growth are poorly understood. Here, we discovered that the Target of Rapamycin (TOR) kinase phosphorylates PYL ABA receptors at a conserved serine residue to prevent activation of the stress response in unstressed plants. This phosphorylation disrupts PYL association with ABA and with PP2C phosphatase effectors, leading to inactivation of SnRK2 kinases...
December 27, 2017: Molecular Cell
Jay C Dunlap, Jennifer J Loros
Some longstanding dogmas in the circadian field warrant reexamination in light of recent studies focused on the role of post-translational modifications and intrinsic disorder in core circadian clock proteins of mice and fungi. Such dogmas include the role of turnover in circadian feedback loops and the origin myths describing evolutionary relatedness among circadian clocks. In this Essay, the authors recapitulate recent findings on circadian clock protein regulation by taking an unconventional approach in the form of a dialog between Wizard and Apprentice...
December 19, 2017: Molecular Cell
Yong Zhu, Xiuye Wang, Elmira Forouzmand, Joshua Jeong, Feng Qiao, Gregory A Sowd, Alan N Engelman, Xiaohui Xie, Klemens J Hertel, Yongsheng Shi
Alternative mRNA processing is a critical mechanism for proteome expansion and gene regulation in higher eukaryotes. The SR family proteins play important roles in splicing regulation. Intriguingly, mammalian genomes encode many poorly characterized SR-like proteins, including subunits of the mRNA 3'-processing factor CFIm, CFIm68 and CFIm59. Here we demonstrate that CFIm functions as an enhancer-dependent activator of mRNA 3' processing. CFIm regulates global alternative polyadenylation (APA) by specifically binding and activating enhancer-containing poly(A) sites (PASs)...
December 18, 2017: Molecular Cell
Thomas J Nicholls, Cristina A Nadalutti, Elisa Motori, Ewen W Sommerville, Gráinne S Gorman, Swaraj Basu, Emily Hoberg, Doug M Turnbull, Patrick F Chinnery, Nils-Göran Larsson, Erik Larsson, Maria Falkenberg, Robert W Taylor, Jack D Griffith, Claes M Gustafsson
How mtDNA replication is terminated and the newly formed genomes are separated remain unknown. We here demonstrate that the mitochondrial isoform of topoisomerase 3α (Top3α) fulfills this function, acting independently of its nuclear role as a component of the Holliday junction-resolving BLM-Top3α-RMI1-RMI2 (BTR) complex. Our data indicate that mtDNA replication termination occurs via a hemicatenane formed at the origin of H-strand replication and that Top3α is essential for resolving this structure. Decatenation is a prerequisite for separation of the segregating unit of mtDNA, the nucleoid, within the mitochondrial network...
December 14, 2017: Molecular Cell
Kobi Simpson-Lavy, Tianchang Xu, Mark Johnston, Martin Kupiec
The ability to respond to available nutrients is critical for all living cells. The AMP-activated protein kinase (SNF1 in yeast) is a central regulator of metabolism that is activated when energy is depleted. We found that SNF1 activity in the nucleus is regulated by controlled relocalization of the SNF1 activator Std1 into puncta. This process is regulated by glucose through the activity of the previously uncharacterized protein kinase Vhs1 and its substrate Sip5, a protein of hitherto unknown function. Phosphorylation of Sip5 prevents its association with Std1 and triggers Std1 accretion...
December 13, 2017: Molecular Cell
Jeongkyu Kim, David Sturgill, Robin Sebastian, Simran Khurana, Andy D Tran, Garrett B Edwards, Alex Kruswick, Sandra Burkett, Eri K Hosogane, William W Hannon, Urbain Weyemi, William M Bonner, Karolin Luger, Philipp Oberdoerffer
Recent integrative epigenome analyses highlight the importance of functionally distinct chromatin states for accurate cell function. How these states are established and maintained is a matter of intense investigation. Here, we present evidence for DNA damage as an unexpected means to shape a protective chromatin environment at regions of recurrent replication stress (RS). Upon aberrant fork stalling, DNA damage signaling and concomitant H2AX phosphorylation coordinate the FACT-dependent deposition of macroH2A1...
December 11, 2017: Molecular Cell
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