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EMBO Journal

Buqing Ye, Benyu Liu, Liuliu Yang, Xiaoxiao Zhu, Dongdong Zhang, Wei Wu, Pingping Zhu, Yanying Wang, Shuo Wang, Pengyan Xia, Ying Du, Shu Meng, Guanling Huang, Jiayi Wu, Runsheng Chen, Yong Tian, Zusen Fan
Divergent long noncoding RNAs (lncRNAs) represent a major lncRNA biotype in mouse and human genomes. The biological and molecular functions of the divergent lncRNAs remain largely unknown. Here, we show that lncKdm2b , a divergent lncRNA for Kdm2b gene, is conserved among five mammalian species and highly expressed in embryonic stem cells (ESCs) and early embryos. LncKdm2b knockout impairs ESC self-renewal and causes early embryonic lethality. LncKdm2b can activate Zbtb3 by promoting the assembly and ATPase activity of Snf2-related CREBBP activator protein (SRCAP) complex in trans Zbtb3 potentiates the ESC self-renewal in a Nanog-dependent manner...
March 13, 2018: EMBO Journal
Andrew J Ewald
No abstract text is available yet for this article.
March 9, 2018: EMBO Journal
Budhaditya Mukherjee, Francesca Tessaro, Juha Vahokoski, Inari Kursula, Jean-Baptiste Marq, Leonardo Scapozza, Dominique Soldati-Favre
Toxoplasma gondii aspartyl protease 3 (TgASP3) phylogenetically clusters with Plasmodium falciparum Plasmepsins IX and X (PfPMIX, PfPMX). These proteases are essential for parasite survival, acting as key maturases for secreted proteins implicated in invasion and egress. A potent antimalarial peptidomimetic inhibitor (49c) originally developed against Plasmepsin II selectively targets TgASP3, PfPMIX, and PfPMX To unravel the molecular basis for the selectivity of 49c, we constructed homology models of PfPMIX, PfPMX, and TgASP3 that were first validated by identifying the determinants of microneme and rhoptry substrate recognition...
March 8, 2018: EMBO Journal
Susanne Herbst, Martin Lorkowski, Olga Sarenko, Thi Kim Loan Nguyen, Tina Jaenicke, Regine Hengge
The nucleotide second messenger c-di-GMP nearly ubiquitously promotes bacterial biofilm formation, with enzymes that synthesize and degrade c-di-GMP being controlled by diverse N-terminal sensor domains. Here, we describe a novel class of widely occurring c-di-GMP phosphodiesterases (PDE) that feature a periplasmic "CSS domain" with two highly conserved cysteines that is flanked by two transmembrane regions (TM1 and TM2) and followed by a cytoplasmic EAL domain with PDE activity. Using PdeC, one of the five CSS domain PDEs of Escherichia coli K-12 , we show that DsbA/DsbB-promoted disulfide bond formation in the CSS domain reduces PDE activity...
March 7, 2018: EMBO Journal
Johanna Fitz, Tobias Neumann, Rushad Pavri
Spt5 is a highly conserved RNA polymerase II (Pol II)-associated pausing and elongation factor. However, its impact on global elongation and Pol II processivity in mammalian cells has not been clarified. Here, we show that depleting Spt5 in mouse embryonic fibroblasts (MEFs) does not cause global elongation defects or decreased elongation rates. Instead, in Spt5-depleted cells, a fraction of Pol II molecules are dislodged during elongation, thus decreasing the number of Pol II complexes that complete the transcription cycle...
March 7, 2018: EMBO Journal
Tobias Brandmann, Hana Fakim, Zoya Padamsi, Ji-Young Youn, Anne-Claude Gingras, Marc R Fabian, Martin Jinek
The LSM domain-containing protein LSM14/Rap55 plays a role in mRNA decapping, translational repression, and RNA granule (P-body) assembly. How LSM14 interacts with the mRNA silencing machinery, including the eIF4E-binding protein 4E-T and the DEAD-box helicase DDX6, is poorly understood. Here we report the crystal structure of the LSM domain of LSM14 bound to a highly conserved C-terminal fragment of 4E-T. The 4E-T C-terminus forms a bi-partite motif that wraps around the N-terminal LSM domain of LSM14. We also determined the crystal structure of LSM14 bound to the C-terminal RecA-like domain of DDX6...
March 6, 2018: EMBO Journal
Selena G Burgess, Manjeet Mukherjee, Sarah Sabir, Nimesh Joseph, Cristina Gutiérrez-Caballero, Mark W Richards, Nicolas Huguenin-Dezot, Jason W Chin, Eileen J Kennedy, Mark Pfuhl, Stephen J Royle, Fanni Gergely, Richard Bayliss
Aurora-A regulates the recruitment of TACC3 to the mitotic spindle through a phospho-dependent interaction with clathrin heavy chain (CHC). Here, we describe the structural basis of these interactions, mediated by three motifs in a disordered region of TACC3. A hydrophobic docking motif binds to a previously uncharacterized pocket on Aurora-A that is blocked in most kinases. Abrogation of the docking motif causes a delay in late mitosis, consistent with the cellular distribution of Aurora-A complexes. Phosphorylation of Ser558 engages a conformational switch in a second motif from a disordered state, needed to bind the kinase active site, into a helical conformation...
March 6, 2018: EMBO Journal
Yanglin Ding, Yuxin Jia, Yiting Shi, Xiaoyan Zhang, Chunpeng Song, Zhizhong Gong, Shuhua Yang
Cold stress is a major environmental factor that negatively affects plant growth and survival. OST1 has been identified as a key protein kinase in plant response to cold stress; however, little is known about the underlying molecular mechanism. In this study, we identified BTF3 and BTF3L (BTF3-like), β-subunits of a nascent polypeptide-associated complex (NAC), as OST1 substrates that positively regulate freezing tolerance. OST1 phosphorylates BTF3 and BTF3L in vitro and in vivo , and facilitates their interaction with C-repeat-binding factors (CBFs) to promote CBF stability under cold stress...
March 5, 2018: EMBO Journal
Ineke Brouwer, Tommaso Moschetti, Andrea Candelli, Edwige B Garcin, Mauro Modesti, Luca Pellegrini, Gijs Jl Wuite, Erwin Jg Peterman
An essential mechanism for repairing DNA double-strand breaks is homologous recombination (HR). One of its core catalysts is human RAD51 (hRAD51), which assembles as a helical nucleoprotein filament on single-stranded DNA, promoting DNA-strand exchange. Here, we study the interaction of hRAD51 with single-stranded DNA using a single-molecule approach. We show that ATP-bound hRAD51 filaments can exist in two different states with different contour lengths and with a free-energy difference of ~4 kB T per hRAD51 monomer...
March 5, 2018: EMBO Journal
Thaneas Prabakaran, Chiranjeevi Bodda, Christian Krapp, Bao-Cun Zhang, Maria H Christensen, Chenglong Sun, Line Reinert, Yujia Cai, Søren B Jensen, Morten K Skouboe, Jens R Nyengaard, Craig B Thompson, Robert Jan Lebbink, Ganes C Sen, Geert van Loo, Rikke Nielsen, Masaaki Komatsu, Lene N Nejsum, Martin R Jakobsen, Mads Gyrd-Hansen, Søren R Paludan
Negative regulation of immune pathways is essential to achieve resolution of immune responses and to avoid excess inflammation. DNA stimulates type I IFN expression through the DNA sensor cGAS, the second messenger cGAMP, and the adaptor molecule STING Here, we report that STING degradation following activation of the pathway occurs through autophagy and is mediated by p62/SQSTM1, which is phosphorylated by TBK1 to direct ubiquitinated STING to autophagosomes. Degradation of STING was impaired in p62-deficient cells, which responded with elevated IFN production to foreign DNA and DNA pathogens...
March 1, 2018: EMBO Journal
Zhen Zhong, Laura Grasso, Caroline Sibilla, Tim J Stevens, Nicholas Barry, Anne Bertolotti
Protein aggregation is a hallmark of diverse neurodegenerative diseases. Multiple lines of evidence have revealed that protein aggregates can penetrate inside cells and spread like prions. How such aggregates enter cells remains elusive. Through a focused siRNA screen targeting genes involved in membrane trafficking, we discovered that mutant SOD1 aggregates, like viruses, exploit cofilin-1 to remodel cortical actin and enter cells. Upstream of cofilin-1, signalling from the RHO GTPase and the ROCK1 and LIMK1 kinases controls cofilin-1 activity to remodel actin and modulate aggregate entry...
March 1, 2018: EMBO Journal
Federico Agostini, Jernej Ule, Julian A Zagalak
No abstract text is available yet for this article.
February 27, 2018: EMBO Journal
Susanne Wegmann, Bahareh Eftekharzadeh, Katharina Tepper, Katarzyna M Zoltowska, Rachel E Bennett, Simon Dujardin, Pawel R Laskowski, Danny MacKenzie, Tarun Kamath, Caitlin Commins, Charles Vanderburg, Allyson D Roe, Zhanyun Fan, Amandine M Molliex, Amayra Hernandez-Vega, Daniel Muller, Anthony A Hyman, Eckhard Mandelkow, J Paul Taylor, Bradley T Hyman
The transition between soluble intrinsically disordered tau protein and aggregated tau in neurofibrillary tangles in Alzheimer's disease is unknown. Here, we propose that soluble tau species can undergo liquid-liquid phase separation (LLPS) under cellular conditions and that phase-separated tau droplets can serve as an intermediate toward tau aggregate formation. We demonstrate that phosphorylated or mutant aggregation prone recombinant tau undergoes LLPS, as does high molecular weight soluble phospho-tau isolated from human Alzheimer brain...
February 22, 2018: EMBO Journal
Spencer G Willet, Mark A Lewis, Zhi-Feng Miao, Dengqun Liu, Megan D Radyk, Rebecca L Cunningham, Joseph Burclaff, Greg Sibbel, Hei-Yong G Lo, Valerie Blanc, Nicholas O Davidson, Zhen-Ning Wang, Jason C Mills
In 1900, Adami speculated that a sequence of context-independent energetic and structural changes governed the reversion of differentiated cells to a proliferative, regenerative state. Accordingly, we show here that differentiated cells in diverse organs become proliferative via a shared program. Metaplasia-inducing injury caused both gastric chief and pancreatic acinar cells to decrease mTORC1 activity and massively upregulate lysosomes/autophagosomes; then increase damage associated metaplastic genes such as Sox9 ; and finally reactivate mTORC1 and re-enter the cell cycle...
February 21, 2018: EMBO Journal
Jan G Ruppert, Kumiko Samejima, Melpomeni Platani, Oscar Molina, Hiroshi Kimura, A Arockia Jeyaprakash, Shinya Ohta, William C Earnshaw
The chromosomal passenger complex (CPC) is directed to centromeres during mitosis via binding to H3T3ph and Sgo1. Whether and how heterochromatin protein 1α (HP1α) influences CPC localisation and function during mitotic entry is less clear. Here, we alter HP1α dynamics by fusing it to a CENP-B DNA-binding domain. Tethered HP1 strongly recruits the CPC, destabilising kinetochore-microtubule interactions and activating the spindle assembly checkpoint. During mitotic exit, the tethered HP1 traps active CPC at centromeres...
February 21, 2018: EMBO Journal
Florian A Horenkamp, Diana P Valverde, Jodi Nunnari, Karin M Reinisch
Lipid transport proteins at membrane contact sites, where two organelles are closely apposed, play key roles in trafficking lipids between cellular compartments while distinct membrane compositions for each organelle are maintained. Understanding the mechanisms underlying non-vesicular lipid trafficking requires characterization of the lipid transporters residing at contact sites. Here, we show that the mammalian proteins in the lipid transfer proteins anchored at a membrane contact site (LAM) family, called GRAMD1a-c, transfer sterols with similar efficiency as the yeast orthologues, which have known roles in sterol transport...
February 21, 2018: EMBO Journal
Alessio Colombo, Hung-En Hsia, Mengzhe Wang, Peer-Hendrik Kuhn, Monika S Brill, Paolo Canevazzi, Regina Feederle, Carla Taveggia, Thomas Misgeld, Stefan F Lichtenthaler
Death receptor 6 (DR6) is an orphan member of the TNF receptor superfamily and controls cell death and differentiation in a cell-autonomous manner in different cell types. Here, we report an additional non-cell-autonomous function for DR6 in the peripheral nervous system (PNS). DR6-knockout (DR6 KO) mice showed precocious myelination in the PNS Using an in vitro myelination assay, we demonstrate that neuronal DR6 acts in trans on Schwann cells (SCs) and reduces SC proliferation and myelination independently of its cytoplasmic death domain...
February 19, 2018: EMBO Journal
José Carlos Santos, Mathias S Dick, Brice Lagrange, Daniel Degrandi, Klaus Pfeffer, Masahiro Yamamoto, Etienne Meunier, Pawel Pelczar, Thomas Henry, Petr Broz
Pathogenic and commensal Gram-negative bacteria produce and release outer membrane vesicles (OMVs), which present several surface antigens and play an important role for bacterial pathogenesis. OMVs also modulate the host immune system, which makes them attractive as vaccine candidates. At the cellular level, OMVs are internalized by macrophages and deliver lipopolysaccharide (LPS) into the host cytosol, thus activating the caspase-11 non-canonical inflammasome. Here, we show that OMV-induced inflammasome activation requires TLR4-TRIF signaling, the production of type I interferons, and the action of guanylate-binding proteins (GBPs), both in macrophages and in vivo Mechanistically, we find that isoprenylated GBPs associate with the surface of OMVs or with transfected LPS, indicating that the key factor that determines GBP recruitment to the Gram-negative bacterial outer membranes is LPS itself...
February 19, 2018: EMBO Journal
Alain Scaiola, Cohue Peña, Melanie Weisser, Daniel Böhringer, Marc Leibundgut, Purnima Klingauf-Nerurkar, Stefan Gerhardy, Vikram Govind Panse, Nenad Ban
Final maturation of eukaryotic ribosomes occurs in the cytoplasm and requires the sequential removal of associated assembly factors and processing of the immature 20S pre-RNA Using cryo-electron microscopy (cryo-EM), we have determined the structure of a yeast cytoplasmic pre-40S particle in complex with Enp1, Ltv1, Rio2, Tsr1, and Pno1 assembly factors poised to initiate final maturation. The structure reveals that the pre-rRNA adopts a highly distorted conformation of its 3' major and 3' minor domains stabilized by the binding of the assembly factors...
February 19, 2018: EMBO Journal
Muriel Amsalem, Corinne Poilbout, Géraldine Ferracci, Patrick Delmas, Francoise Padilla
Cholesterol is a major lipid component of the mammalian plasma membrane. While much is known about its metabolism, its transport, and its role in atherosclerotic vascular disease, less is known about its role in neuronal pathophysiology. This study reveals an unexpected function of cholesterol in controlling pain transmission. We show that inflammation lowers cholesterol content in skin tissue and sensory DRG culture. Pharmacological depletion of cellular cholesterol entails sensitization of nociceptive neurons and promotes mechanical and thermal hyperalgesia through the activation of voltage-gated Nav1...
February 19, 2018: EMBO Journal
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