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EMBO Journal

Florence Husada, Kiran Bountra, Konstantinos Tassis, Marijn de Boer, Maria Romano, Sylvie Rebuffat, Konstantinos Beis, Thorben Cordes
ABC transporters utilize ATP for export processes to provide cellular resistance against toxins, antibiotics, and harmful metabolites in eukaryotes and prokaryotes. Based on static structure snapshots, it is believed that they use an alternating access mechanism, which couples conformational changes to ATP binding (outward-open conformation) and hydrolysis (inward-open) for unidirectional transport driven by ATP Here, we analyzed the conformational states and dynamics of the antibacterial peptide exporter McjD from Escherichia coli using single-molecule Förster resonance energy transfer (smFRET)...
September 20, 2018: EMBO Journal
Masashi Sugo, Hana Kimura, Kohei Arasaki, Toshiki Amemiya, Naohiko Hirota, Naoshi Dohmae, Yuzuru Imai, Tsuyoshi Inoshita, Kahori Shiba-Fukushima, Nobutaka Hattori, Jinglei Cheng, Toyoshi Fujimoto, Yuichi Wakana, Hiroki Inoue, Mitsuo Tagaya
PGAM5, a mitochondrial protein phosphatase that is genetically and biochemically linked to PINK1, facilitates mitochondrial division by dephosphorylating the mitochondrial fission factor Drp1. At the onset of mitophagy, PGAM5 is cleaved by PARL, a rhomboid protease that degrades PINK1 in healthy cells, and the cleaved form facilitates the engulfment of damaged mitochondria by autophagosomes by dephosphorylating the mitophagy receptor FUNDC1. Here, we show that the function and localization of PGAM5 are regulated by syntaxin 17 (Stx17), a mitochondria-associated membrane/mitochondria protein implicated in mitochondrial dynamics in fed cells and autophagy in starved cells...
September 20, 2018: EMBO Journal
Thomas H Söllner, Jörg Malsam
No abstract text is available yet for this article.
September 20, 2018: EMBO Journal
Masayuki Tsuzuki, Andrzej T Wierzbicki
No abstract text is available yet for this article.
September 20, 2018: EMBO Journal
Götz Hartleben, Christine Müller, Andreas Krämer, Heiko Schimmel, Laura M Zidek, Carsten Dornblut, René Winkler, Sabrina Eichwald, Gertrud Kortman, Christian Kosan, Joost Kluiver, Iver Petersen, Anke van den Berg, Zhao-Qi Wang, Cornelis F Calkhoven
The tuberous sclerosis complex (TSC) 1/2 is a negative regulator of the nutrient-sensing kinase mechanistic target of rapamycin complex (mTORC1), and its function is generally associated with tumor suppression. Nevertheless, biallelic loss of function of TSC1 or TSC2 is rarely found in malignant tumors. Here, we show that TSC1/2 is highly expressed in Burkitt's lymphoma cell lines and patient samples of human Burkitt's lymphoma, a prototypical MYC-driven cancer. Mechanistically, we show that MYC induces TSC1 expression by transcriptional activation of the TSC1 promoter and repression of miR-15a...
September 20, 2018: EMBO Journal
Jianxiang Chen, Muthukumar Rajasekaran, Hongping Xia, Shik Nie Kong, Amudha Deivasigamani, Karthik Sekar, Hengjun Gao, Hannah Lf Swa, Jayantha Gunaratne, London Lucien Ooi, Tian Xie, Wanjin Hong, Kam Man Hui
Uncontrolled cell division is a hallmark of cancer. Deregulation of Wnt components has been linked to aberrant cell division by multiple mechanisms, including Wnt-mediated stabilisation of proteins signalling, which was notably observed in mitosis. Analysis of Wnt components revealed an unexpected role of B-cell CLL/lymphoma 9 (BCL9) in maintaining mitotic Wnt signalling to promote precise cell division and growth of cancer cell. Mitotic interactome analysis revealed a mechanistic role of BCL9 in inhibiting clathrin-mediated degradation of LRP6 signalosome components by interacting with clathrin and the components in Wnt destruction complex; this function was further controlled by CDK1-driven phosphorylation of BCL9 N-terminal, especially T172...
September 14, 2018: EMBO Journal
Gaurav Pathria, David A Scott, Yongmei Feng, Joo Sang Lee, Yu Fujita, Gao Zhang, Avinash D Sahu, Eytan Ruppin, Meenhard Herlyn, Andrei L Osterman, Ze'ev A Ronai
Nutrient restriction reprograms cellular signaling and metabolic network to shape cancer phenotype. Lactate dehydrogenase A (LDHA) has a key role in aerobic glycolysis (the Warburg effect) through regeneration of the electron acceptor NAD+ and is widely regarded as a desirable target for cancer therapeutics. However, the mechanisms of cellular response and adaptation to LDHA inhibition remain largely unknown. Here, we show that LDHA activity supports serine and aspartate biosynthesis. Surprisingly, however, LDHA inhibition fails to impact human melanoma cell proliferation, survival, or tumor growth...
September 12, 2018: EMBO Journal
Alán Alpár, Péter Zahola, János Hanics, Zsófia Hevesi, Solomiia Korchynska, Marco Benevento, Christian Pifl, Gergely Zachar, Jessica Perugini, Ilenia Severi, Patrick Leitgeb, Joanne Bakker, Andras G Miklosi, Evgenii Tretiakov, Erik Keimpema, Gloria Arque, Ramon O Tasan, Günther Sperk, Katarzyna Malenczyk, Zoltán Máté, Ferenc Erdélyi, Gábor Szabó, Gert Lubec, Miklós Palkovits, Antonio Giordano, Tomas Gm Hökfelt, Roman A Romanov, Tamas L Horvath, Tibor Harkany
Stress-induced cortical alertness is maintained by a heightened excitability of noradrenergic neurons innervating, notably, the prefrontal cortex. However, neither the signaling axis linking hypothalamic activation to delayed and lasting noradrenergic excitability nor the molecular cascade gating noradrenaline synthesis is defined. Here, we show that hypothalamic corticotropin-releasing hormone-releasing neurons innervate ependymal cells of the 3rd ventricle to induce ciliary neurotrophic factor (CNTF) release for transport through the brain's aqueductal system...
September 12, 2018: EMBO Journal
Fatma Ayhan, Barbara A Perez, Hannah K Shorrock, Tao Zu, Monica Banez-Coronel, Tammy Reid, Hirokazu Furuya, H Brent Clark, Juan C Troncoso, Christopher A Ross, S H Subramony, Tetsuo Ashizawa, Eric T Wang, Anthony T Yachnis, Laura Pw Ranum
Spinocerebellar ataxia type 8 (SCA8) is caused by a bidirectionally transcribed CTG·CAG expansion that results in the in vivo accumulation of CUG RNA foci, an ATG-initiated polyGln and a polyAla protein expressed by repeat-associated non-ATG (RAN) translation. Although RAN proteins have been reported in a growing number of diseases, the mechanisms and role of RAN translation in disease are poorly understood. We report a novel toxic SCA8 polySer protein which accumulates in white matter (WM) regions as aggregates that increase with age and disease severity...
September 11, 2018: EMBO Journal
Claudia M Persoon, Alessandro Moro, Joris P Nassal, Margherita Farina, Jurjen H Broeke, Swati Arora, Natalia Dominguez, Jan Rt van Weering, Ruud F Toonen, Matthijs Verhage
Neuropeptides are essential signaling molecules transported and secreted by dense-core vesicles (DCVs), but the number of DCVs available for secretion, their subcellular distribution, and release probability are unknown. Here, we quantified DCV pool sizes in three types of mammalian CNS neurons in vitro and in vivo Super-resolution and electron microscopy reveal a total pool of 1,400-18,000 DCVs, correlating with neurite length. Excitatory hippocampal and inhibitory striatal neurons in vitro have a similar DCV density, and thalamo-cortical axons in vivo have a slightly higher density...
September 5, 2018: EMBO Journal
Yu-Chen Guo, Meng-Yuan Wang, Shi-Wen Zhang, Yun-Shu Wu, Chen-Chen Zhou, Ri-Xin Zheng, Bin Shao, Yuan Wang, Liang Xie, Wei-Qing Liu, Ning-Yuan Sun, Jun-Jun Jing, Ling Ye, Qian-Ming Chen, Quan Yuan
The osteogenic differentiation of mesenchymal stem cells (MSCs) is governed by multiple mechanisms. Growing evidence indicates that ubiquitin-dependent protein degradation is critical for the differentiation of MSCs and bone formation; however, the function of ubiquitin-specific proteases, the largest subfamily of deubiquitylases, remains unclear. Here, we identify USP34 as a previously unknown regulator of osteogenesis. The expression of USP34 in human MSCs increases after osteogenic induction while depletion of USP34 inhibits osteogenic differentiation...
September 4, 2018: EMBO Journal
Michael James Apta-Smith, Juan Ramon Hernandez-Fernaud, Andrew James Bowman
Newly synthesised histones are thought to dimerise in the cytosol and undergo nuclear import in complex with histone chaperones. Here, we provide evidence that human H3.1 and H4 are imported into the nucleus as monomers. Using a tether-and-release system to study the import dynamics of newly synthesised histones, we find that cytosolic H3.1 and H4 can be maintained as stable monomeric units. Cytosolically tethered histones are bound to importin-alpha proteins (predominantly IPO4), but not to histone-specific chaperones NASP, ASF1a, RbAp46 (RBBP7) or HAT1, which reside in the nucleus in interphase cells...
September 3, 2018: EMBO Journal
Hui-Feng Chen, Chen-Ming Hsu, Yi-Shuian Huang
Expression of mitochondrial proton transporter uncoupling protein 1 (UCP1) in brown adipose tissue (BAT) is essential for mammalian thermogenesis. While human UCP1 mRNA exists in a long form only, alternative polyadenylation creates two different isoforms in mice with 10% of UCP1 mRNA found in the long form (Ucp1L) and ~90% in the short form (Ucp1S). We generated a mouse model expressing only Ucp1S and found that it showed impaired thermogenesis due to a 60% drop in UCP1 protein levels, suggesting that Ucp1L is more efficiently translated than Ucp1S...
September 3, 2018: EMBO Journal
João Vaz-Silva, Patrícia Gomes, Qi Jin, Mei Zhu, Viktoriya Zhuravleva, Sebastian Quintremil, Torcato Meira, Joana Silva, Chrysoula Dioli, Carina Soares-Cunha, Nikolaos P Daskalakis, Nuno Sousa, Ioannis Sotiropoulos, Clarissa L Waites
Emerging studies implicate Tau as an essential mediator of neuronal atrophy and cognitive impairment in Alzheimer's disease (AD), yet the factors that precipitate Tau dysfunction in AD are poorly understood. Chronic environmental stress and elevated glucocorticoids (GC), the major stress hormones, are associated with increased risk of AD and have been shown to trigger intracellular Tau accumulation and downstream Tau-dependent neuronal dysfunction. However, the mechanisms through which stress and GC disrupt Tau clearance and degradation in neurons remain unclear...
August 30, 2018: EMBO Journal
Yusheng Wu, Wenwei Zhao, Yang Liu, Xiangtian Tan, Xin Li, Qin Zou, Zhengtao Xiao, Hui Xu, Yuting Wang, Xuerui Yang
Elevated expression of RNA binding protein HNRNPC has been reported in cancer cells, while the essentialness and functions of HNRNPC in tumors were not clear. We showed that repression of HNRNPC in the breast cancer cells MCF7 and T47D inhibited cell proliferation and tumor growth. Our computational inference of the key pathways and extensive experimental investigations revealed that the cascade of interferon responses mediated by RIG-I was responsible for such tumor-inhibitory effect. Interestingly, repression of HNRNPC resulted in accumulation of endogenous double-stranded RNA (dsRNA), the binding ligand of RIG-I...
August 29, 2018: EMBO Journal
Julien Bacal, María Moriel-Carretero, Benjamin Pardo, Antoine Barthe, Sushma Sharma, Andrei Chabes, Armelle Lengronne, Philippe Pasero
The S-phase checkpoint maintains the integrity of the genome in response to DNA replication stress. In budding yeast, this pathway is initiated by Mec1 and is amplified through the activation of Rad53 by two checkpoint mediators: Mrc1 promotes Rad53 activation at stalled forks, and Rad9 is a general mediator of the DNA damage response. Here, we have investigated the interplay between Mrc1 and Rad9 in response to DNA damage and found that they control DNA replication through two distinct but complementary mechanisms...
August 29, 2018: EMBO Journal
Lijing Xing, Yan Liu, Shujuan Xu, Jun Xiao, Bo Wang, Hanwen Deng, Zhuang Lu, Yunyuan Xu, Kang Chong
Post-translational modification of proteins by O -linked β- N -acetylglucosamine ( O -GlcNAc) is catalyzed by O -GlcNAc transferases (OGTs). O -GlcNAc modification of proteins regulates multiple important biological processes in metazoans. However, whether protein O -GlcNAcylation is involved in epigenetic processes during plant development is largely unknown. Here, we show that loss of function of SECRET AGENT (SEC), an OGT in Arabidopsis , leads to an early flowering phenotype. This results from reduced histone H3 lysine 4 trimethylation (H3K4me3) of FLOWERING LOCUS C ( FLC ) locus, which encodes a key negative regulator of flowering...
August 27, 2018: EMBO Journal
Elena Tomasello, Karima Naciri, Rabie Chelbi, Gilles Bessou, Anissa Fries, Elise Gressier, Abdenour Abbas, Emeline Pollet, Philippe Pierre, Toby Lawrence, Thien-Phong Vu Manh, Marc Dalod
Plasmacytoid dendritic cells (pDC) are the major source of type I interferons (IFN-I) during viral infections, in response to triggering of endosomal Toll-like receptors (TLRs) 7 or 9 by viral single-stranded RNA or unmethylated CpG DNA, respectively. Synthetic ligands have been used to disentangle the underlying signaling pathways. The adaptor protein AP3 is necessary to transport molecular complexes of TLRs, synthetic CpG DNA, and MyD88 into endosomal compartments allowing interferon regulatory factor 7 (IRF7) recruitment whose phosphorylation then initiates IFN-I production...
August 21, 2018: EMBO Journal
Massimo D'Agostino, Herre Jelger Risselada, Laura J Endter, Véronique Comte-Miserez, Andreas Mayer
Constitutive membrane fusion within eukaryotic cells is thought to be controlled at its initial steps, membrane tethering and SNARE complex assembly, and to rapidly proceed from there to full fusion. Although theory predicts that fusion pore expansion faces a major energy barrier and might hence be a rate-limiting and regulated step, corresponding states with non-expanding pores are difficult to assay and have remained elusive. Here, we show that vacuoles in living yeast are connected by a metastable, non-expanding, nanoscopic fusion pore...
August 17, 2018: EMBO Journal
Cecile Evrin, Joseph D Maman, Aurora Diamante, Luca Pellegrini, Karim Labib
The eukaryotic replisome disassembles parental chromatin at DNA replication forks, but then plays a poorly understood role in the re-deposition of the displaced histone complexes onto nascent DNA. Here, we show that yeast DNA polymerase α contains a histone-binding motif that is conserved in human Pol α and is specific for histones H2A and H2B. Mutation of this motif in budding yeast cells does not affect DNA synthesis, but instead abrogates gene silencing at telomeres and mating-type loci. Similar phenotypes are produced not only by mutations that displace Pol α from the replisome, but also by mutation of the previously identified histone-binding motif in the CMG helicase subunit Mcm2, the human orthologue of which was shown to bind to histones H3 and H4...
August 13, 2018: EMBO Journal
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