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EMBO Journal

Jeffrey S Mugridge, John D Gross
No abstract text is available yet for this article.
November 19, 2018: EMBO Journal
Tata Nageswara Rao, Manoj K Gupta, Samir Softic, Leo D Wang, Young C Jang, Thomas Thomou, Olivier Bezy, Rohit N Kulkarni, C Ronald Kahn, Amy J Wagers
A finely tuned balance of self-renewal, differentiation, proliferation, and survival governs the pool size and regenerative capacity of blood-forming hematopoietic stem and progenitor cells (HSPCs). Here, we report that protein kinase C delta (PKCδ) is a critical regulator of adult HSPC number and function that couples the proliferative and metabolic activities of HSPCs. PKCδ-deficient mice showed a pronounced increase in HSPC numbers, increased competence in reconstituting lethally irradiated recipients, enhanced long-term competitive advantage in serial transplantation studies, and an augmented HSPC recovery during stress...
November 16, 2018: EMBO Journal
Tara Ec Condos, Karen M Dunkerley, E Aisha Freeman, Kathryn R Barber, Jacob D Aguirre, Viduth K Chaugule, Yiming Xiao, Lars Konermann, Helen Walden, Gary S Shaw
The E3 ligase parkin ubiquitinates outer mitochondrial membrane proteins during oxidative stress and is linked to early-onset Parkinson's disease. Parkin is autoinhibited but is activated by the kinase PINK1 that phosphorylates ubiquitin leading to parkin recruitment, and stimulates phosphorylation of parkin's N-terminal ubiquitin-like (pUbl) domain. How these events alter the structure of parkin to allow recruitment of an E2~Ub conjugate and enhanced ubiquitination is an unresolved question. We present a model of an E2~Ub conjugate bound to the phospho-ubiquitin-loaded C-terminus of parkin, derived from NMR chemical shift perturbation experiments...
November 16, 2018: EMBO Journal
Daniel Krueger, Pietro Tardivo, Congtin Nguyen, Stefano De Renzis
Tissue invagination drives embryo remodeling and assembly of internal organs during animal development. While the role of actomyosin-mediated apical constriction in initiating inward folding is well established, computational models suggest relaxation of the basal surface as an additional requirement. However, the lack of genetic mutations interfering specifically with basal relaxation has made it difficult to test its requirement during invagination so far. Here we use optogenetics to quantitatively control myosin-II levels at the basal surface of invaginating cells during Drosophila gastrulation...
November 15, 2018: EMBO Journal
Yanglin Ding, Jian Lv, Yiting Shi, Junping Gao, Jian Hua, Chunpeng Song, Zhizhong Gong, Shuhua Yang
OST1 (open stomata 1) protein kinase plays a central role in regulating freezing tolerance in Arabidopsis ; however, the mechanism underlying cold activation of OST1 remains unknown. Here, we report that a plasma membrane-localized clade-E growth-regulating 2 (EGR2) phosphatase interacts with OST1 and inhibits OST1 activity under normal conditions. EGR2 is N-myristoylated by N-myristoyltransferase NMT1 at 22°C, which is important for its interaction with OST1. Moreover, myristoylation of EGR2 is required for its function in plant freezing tolerance...
November 14, 2018: EMBO Journal
Nikolaos Doumpas, Franziska Lampart, Mark D Robinson, Antonio Lentini, Colm E Nestor, Claudio Cantù, Konrad Basler
During canonical Wnt signalling, the activity of nuclear β-catenin is largely mediated by the TCF/LEF family of transcription factors. To challenge this view, we used the CRISPR/Cas9 genome editing approach to generate HEK 293T cell clones lacking all four TCF/LEF genes. By performing unbiased whole transcriptome sequencing analysis, we found that a subset of β-catenin transcriptional targets did not require TCF/LEF factors for their regulation. Consistent with this finding, we observed in a genome-wide analysis that β-catenin occupied specific genomic regions in the absence of TCF/LEF Finally, we revealed the existence of a transcriptional activity of β-catenin that specifically appears when TCF/LEF factors are absent, and refer to this as β-catenin-GHOST response...
November 13, 2018: EMBO Journal
Talha Rashid, Ivan Nemazanyy, Cecilia Paolini, Takashi Tatsuta, Paul Crespin, Delphine de Villeneuve, Susanne Brodesser, Paule Benit, Pierre Rustin, Martin A Baraibar, Onnik Agbulut, Anne Olivier, Feliciano Protasi, Thomas Langer, Roman Chrast, Pascale de Lonlay, Helene de Foucauld, Bert Blaauw, Mario Pende
As a consequence of impaired glucose or fatty acid metabolism, bioenergetic stress in skeletal muscles may trigger myopathy and rhabdomyolysis. Genetic mutations causing loss of function of the LPIN1 gene frequently lead to severe rhabdomyolysis bouts in children, though the metabolic alterations and possible therapeutic interventions remain elusive. Here, we show that lipin1 deficiency in mouse skeletal muscles is sufficient to trigger myopathy. Strikingly, muscle fibers display strong accumulation of both neutral and phospholipids...
November 12, 2018: EMBO Journal
Vandana Shashi, Maria M Magiera, Dennis Klein, Maha Zaki, Kelly Schoch, Sabine Rudnik-Schöneborn, Andrew Norman, Osorio Lopes Abath Neto, Marina Dusl, Xidi Yuan, Luca Bartesaghi, Patrizia De Marco, Ahmed A Alfares, Ronit Marom, Stefan T Arold, Francisco J Guzmán-Vega, Loren Dm Pena, Edward C Smith, Maja Steinlin, Mohamed Oe Babiker, Payam Mohassel, A Reghan Foley, Sandra Donkervoort, Rupleen Kaur, Partha S Ghosh, Valentina Stanley, Damir Musaev, Caroline Nava, Cyril Mignot, Boris Keren, Marcello Scala, Elisa Tassano, Paolo Picco, Paola Doneda, Chiara Fiorillo, Mahmoud Y Issa, Ali Alassiri, Ahmed Alahmad, Amanda Gerard, Pengfei Liu, Yaping Yang, Birgit Ertl-Wagner, Peter G Kranz, Ingrid M Wentzensen, Rolf Stucka, Nicholas Stong, Andrew S Allen, David B Goldstein, Benedikt Schoser, Kai M Rösler, Majid Alfadhel, Valeria Capra, Roman Chrast, Tim M Strom, Erik-Jan Kamsteeg, Carsten G Bönnemann, Joseph G Gleeson, Rudolf Martini, Carsten Janke, Jan Senderek
A set of glutamylases and deglutamylases controls levels of tubulin polyglutamylation, a prominent post-translational modification of neuronal microtubules. Defective tubulin polyglutamylation was first linked to neurodegeneration in the Purkinje cell degeneration ( pcd ) mouse, which lacks deglutamylase CCP1, displays massive cerebellar atrophy, and accumulates abnormally glutamylated tubulin in degenerating neurons. We found biallelic rare and damaging variants in the gene encoding CCP1 in 13 individuals with infantile-onset neurodegeneration and confirmed the absence of functional CCP1 along with dysregulated tubulin polyglutamylation...
November 12, 2018: EMBO Journal
Maria M Magiera, Satish Bodakuntla, Jakub Žiak, Sabrina Lacomme, Patricia Marques Sousa, Sophie Leboucher, Torben J Hausrat, Christophe Bosc, Annie Andrieux, Matthias Kneussel, Marc Landry, André Calas, Martin Balastik, Carsten Janke
Posttranslational modifications of tubulin are emerging regulators of microtubule functions. We have shown earlier that upregulated polyglutamylation is linked to rapid degeneration of Purkinje cells in mice with a mutation in the deglutamylating enzyme CCP1. How polyglutamylation leads to degeneration, whether it affects multiple neuron types, or which physiological processes it regulates in healthy neurons has remained unknown. Here, we demonstrate that excessive polyglutamylation induces neurodegeneration in a cell-autonomous manner and can occur in many parts of the central nervous system...
November 12, 2018: EMBO Journal
Jean-Baptiste Esmenjaud, David Stroebel, Kelvin Chan, Teddy Grand, Mélissa David, Lonnie P Wollmuth, Antoine Taly, Pierre Paoletti
NMDA receptors (NMDARs) are glutamate-gated ion channels that are key mediators of excitatory neurotransmission and synaptic plasticity throughout the central nervous system. They form massive heterotetrameric complexes endowed with unique allosteric capacity provided by eight extracellular clamshell-like domains arranged as two superimposed layers. Despite an increasing number of full-length NMDAR structures, how these domains cooperate in an intact receptor to control its activity remains poorly understood...
November 5, 2018: EMBO Journal
Ailing Wu, Qingzhe Wu, Yujie Deng, Yuning Liu, Jinqiu Lu, Liansheng Liu, Xiaoling Li, Cheng Liao, Bin Zhao, Hai Song
Targeting immune checkpoints, such as PD-L1 and its receptor PD-1, has opened a new avenue for treating cancers. Understanding the regulatory mechanism of PD-L1 and PD-1 will improve the clinical response rate and efficacy of PD-1/PD-L1 blockade in cancer patients and the development of combinatorial strategies. VGLL4 inhibits YAP-induced cell proliferation and tumorigenesis through competition with YAP for binding to TEADs. However, whether VGLL4 has a role in anti-tumor immunity is largely unknown. Here, we found that disruption of Vgll4 results in potent T cell-mediated tumor regression in murine syngeneic models...
November 5, 2018: EMBO Journal
Giuliana Fossati, Davide Pozzi, Alice Canzi, Filippo Mirabella, Sonia Valentino, Raffaella Morini, Elsa Ghirardini, Fabia Filipello, Milena Moretti, Cecilia Gotti, Douglas S Annis, Deane F Mosher, Cecilia Garlanda, Barbara Bottazzi, Giulia Taraboletti, Alberto Mantovani, Michela Matteoli, Elisabetta Menna
Control of synapse number and function in the developing central nervous system is critical to the formation of neural circuits. Astrocytes play a key role in this process by releasing factors that promote the formation of excitatory synapses. Astrocyte-secreted thrombospondins (TSPs) induce the formation of structural synapses, which however remain post-synaptically silent, suggesting that completion of early synaptogenesis may require a two-step mechanism. Here, we show that the humoral innate immune molecule Pentraxin 3 (PTX3) is expressed in the developing rodent brain...
November 5, 2018: EMBO Journal
Daniel Keppeler, Ricardo Martins Merino, David Lopez de la Morena, Burak Bali, Antoine Tarquin Huet, Anna Gehrt, Christian Wrobel, Swati Subramanian, Tobias Dombrowski, Fred Wolf, Vladan Rankovic, Andreas Neef, Tobias Moser
Optogenetic tools, providing non-invasive control over selected cells, have the potential to revolutionize sensory prostheses for humans. Optogenetic stimulation of spiral ganglion neurons (SGNs) in the ear provides a future alternative to electrical stimulation used in cochlear implants. However, most channelrhodopsins do not support the high temporal fidelity pertinent to auditory coding because they require milliseconds to close after light-off. Here, we biophysically characterized the fast channelrhodopsin Chronos and revealed a deactivation time constant of less than a millisecond at body temperature...
November 5, 2018: EMBO Journal
Cristina Martínez, Ana Espinosa-Ruíz, Miguel de Lucas, Stella Bernardo-García, José M Franco-Zorrilla, Salomé Prat
The Arabidopsis PIF4 and BES1/BZR1 transcription factors antagonize light signaling by facilitating co-activated expression of a large number of cell wall-loosening and auxin-related genes. While PIF4 directly activates expression of these targets, BES1 and BZR1 activity switch from a repressive to an activator function, depending on interaction with TOPLESS and other families of regulators including PIFs. However, the complexity of this regulation and its role in diurnal control of plant growth and brassinosteroid (BR) levels is little understood...
November 2, 2018: EMBO Journal
Ekaterina A Anedchenko, Anke Samel-Pommerencke, Tra My Tran Nguyen, Sara Shahnejat-Bushehri, Juliane Pöpsel, Daniel Lauster, Andreas Herrmann, Juri Rappsilber, Alessandro Cuomo, Tiziana Bonaldi, Ann E Ehrenhofer-Murray
Kinetochores are supramolecular assemblies that link centromeres to microtubules for sister chromatid segregation in mitosis. For this, the inner kinetochore CCAN/Ctf19 complex binds to centromeric chromatin containing the histone variant CENP-A, but whether the interaction of kinetochore components to centromeric nucleosomes is regulated by posttranslational modifications is unknown. Here, we investigated how methylation of arginine 37 (R37Me) and acetylation of lysine 49 (K49Ac) on the CENP-A homolog Cse4 from Saccharomyces cerevisiae regulate molecular interactions at the inner kinetochore...
November 2, 2018: EMBO Journal
Stephanie L Sarbanes, Jérémie Le Pen, Charles M Rice
No abstract text is available yet for this article.
November 2, 2018: EMBO Journal
Caroline Tawk, Giulia Nigro, Ines Rodrigues Lopes, Carmen Aguilar, Clivia Lisowski, Miguel Mano, Philippe Sansonetti, Jörg Vogel, Ana Eulalio
While mucosal inflammation is a major source of stress during enteropathogen infection, it remains to be fully elucidated how the host benefits from this environment to clear the pathogen. Here, we show that host stress induced by different stimuli mimicking inflammatory conditions strongly reduces the binding of Shigella flexneri to epithelial cells. Mechanistically, stress activates acid sphingomyelinase leading to host membrane remodeling. Consequently, knockdown or pharmacological inhibition of the acid sphingomyelinase blunts the stress-dependent inhibition of Shigella binding to host cells...
November 2, 2018: EMBO Journal
Patrick A Eyers
No abstract text is available yet for this article.
October 30, 2018: EMBO Journal
Marco Gaviraghi, Claudia Vivori, Yerma Pareja Sanchez, Francesca Invernizzi, Angela Cattaneo, Benedetta Maria Santoliquido, Michela Frenquelli, Simona Segalla, Angela Bachi, Claudio Doglioni, Vicent Pelechano, Davide Cittaro, Giovanni Tonon
Focal deletions occur frequently in the cancer genome. However, the putative tumor-suppressive genes residing within these regions have been difficult to pinpoint. To robustly identify these genes, we implemented a computational approach based on non-negative matrix factorization, NMF, and interrogated the TCGA dataset. This analysis revealed a metagene signature including a small subset of genes showing pervasive hemizygous deletions, reduced expression in cancer patient samples, and nucleolar function. Amid the genes belonging to this signature, we have identified PNRC1, a nuclear receptor coactivator...
October 29, 2018: EMBO Journal
Jun Zhi Er, Ricky Abdi Gunawan Koean, Jeak Ling Ding
The transcription factor, T-bet, regulates type 1 inflammatory responses against a range of infections. Here, we demonstrate a previously unaddressed role of T-bet, to influenza virus and bacterial superinfection. Interestingly, we found that T-bet deficiency did not adversely affect the efficacy of viral clearance or recovery compared to wild-type hosts. Instead, increased infiltration of neutrophils and production of Th17 cytokines (IL-17 and IL-22), in lungs of influenza virus-infected T-bet-/- mice, were correlated with survival advantage against subsequent infection by Streptococcus pneumoniae Neutralization of IL-17, but not IL-22, in T-bet-/- mice increased pulmonary bacterial load, concomitant with decreased neutrophil infiltration and reduced survival of T-bet-/- mice...
October 15, 2018: EMBO Journal
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