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EMBO Journal

Paul Ginsparg
No abstract text is available yet for this article.
October 19, 2016: EMBO Journal
Chrisovalantis Papadopoulos, Philipp Kirchner, Monika Bug, Daniel Grum, Lisa Koerver, Nina Schulze, Robert Poehler, Alina Dressler, Sven Fengler, Khalid Arhzaouy, Vanda Lux, Michael Ehrmann, Conrad C Weihl, Hemmo Meyer
Rupture of endosomes and lysosomes is a major cellular stress condition leading to cell death and degeneration. Here, we identified an essential role for the ubiquitin-directed AAA-ATPase, p97, in the clearance of damaged lysosomes by autophagy. Upon damage, p97 translocates to lysosomes and there cooperates with a distinct set of cofactors including UBXD1, PLAA, and the deubiquitinating enzyme YOD1, which we term ELDR components for Endo-Lysosomal Damage Response. Together, they act downstream of K63-linked ubiquitination and p62 recruitment, and selectively remove K48-linked ubiquitin conjugates from a subpopulation of damaged lysosomes to promote autophagosome formation...
October 17, 2016: EMBO Journal
Meidi Gu, Zhiyong Liu, Rongrong Lai, Si Liu, Wenlong Lin, Chuan Ouyang, Sheng Ye, He Huang, Xiaojian Wang
TANK-binding kinase 1 (TBK1) activation is a central event in type I interferon production in anti-virus innate immunity. However, the regulatory mechanism underlying TBK1 activation remains unclear. Here we report that Raf kinase inhibitory protein (RKIP) is essential for TBK1 activation and type I interferon production triggered by viral infection. Upon viral infection, RKIP is phosphorylated at serine 109 (S109) by TBK1. Phosphorylation of RKIP enhances its interaction with TBK1 and in turn promotes TBK1 autophosphorylation...
October 17, 2016: EMBO Journal
Pavel Hanč, Oliver Schulz, Hanna Fischbach, Stephen R Martin, Svend Kjær, Caetano Reis E Sousa
DNGR-1 is receptor expressed by certain dendritic cell (DC) subsets and by DC precursors in mouse. It possesses a C-type lectin-like domain (CTLD) followed by a poorly characterized neck region coupled to a transmembrane region and short intracellular tail. The CTLD of DNGR-1 binds F-actin exposed by dead cell corpses and causes the receptor to signal and potentiate cross-presentation of dead cell-associated antigens by DCs. Here, we describe a conformational change that occurs in the neck region of DNGR-1 in a pH- and ionic strength-dependent manner and that controls cross-presentation of dead cell-associated antigens...
October 17, 2016: EMBO Journal
Brant M Webster, David J Thaller, Jens Jäger, Sarah E Ochmann, Sapan Borah, C Patrick Lusk
The integrity of the nuclear envelope barrier relies on membrane remodeling by the ESCRTs, which seal nuclear envelope holes and contribute to the quality control of nuclear pore complexes (NPCs); whether these processes are mechanistically related remains poorly defined. Here, we show that the ESCRT-II/III chimera, Chm7, is recruited to a nuclear envelope subdomain that expands upon inhibition of NPC assembly and is required for the formation of the storage of improperly assembled NPCs (SINC) compartment. Recruitment to sites of NPC assembly is mediated by its ESCRT-II domain and the LAP2-emerin-MAN1 (LEM) family of integral inner nuclear membrane proteins, Heh1 and Heh2...
October 12, 2016: EMBO Journal
Madalena M Reimão-Pinto, Raphael A Manzenreither, Thomas R Burkard, Pawel Sledz, Martin Jinek, Karl Mechtler, Stefan L Ameres
The posttranscriptional addition of nucleotides to the 3' end of RNA regulates the maturation, function, and stability of RNA species in all domains of life. Here, we show that in flies, 3' terminal RNA uridylation triggers the processive, 3'-to-5' exoribonucleolytic decay via the RNase II/R enzyme CG16940, a homolog of the human Perlman syndrome exoribonuclease Dis3l2. Together with the TUTase Tailor, dmDis3l2 forms the cytoplasmic, terminal RNA uridylation-mediated processing (TRUMP) complex that functionally cooperates in the degradation of structured RNA RNA immunoprecipitation and high-throughput sequencing reveals a variety of TRUMP complex substrates, including abundant non-coding RNA, such as 5S rRNA, tRNA, snRNA, snoRNA, and the essential RNase MRP Based on genetic and biochemical evidence, we propose a key function of the TRUMP complex in the cytoplasmic quality control of RNA polymerase III transcripts...
October 11, 2016: EMBO Journal
Nicola Strenzke, Rituparna Chakrabarti, Hanan Al-Moyed, Alexandra Müller, Gerhard Hoch, Tina Pangrsic, Gulnara Yamanbaeva, Christof Lenz, Kuan-Ting Pan, Elisabeth Auge, Ruth Geiss-Friedlander, Henning Urlaub, Nils Brose, Carolin Wichmann, Ellen Reisinger
The multi-C2 domain protein otoferlin is required for hearing and mutated in human deafness. Some OTOF mutations cause a mild elevation of auditory thresholds but strong impairment of speech perception. At elevated body temperature, hearing is lost. Mice homozygous for one of these mutations, Otof(I515T/I515T), exhibit a moderate hearing impairment involving enhanced adaptation to continuous or repetitive sound stimulation. In Otof(I515T/I515T) inner hair cells (IHCs), otoferlin levels are diminished by 65%, and synaptic vesicles are enlarged...
October 11, 2016: EMBO Journal
Juan Pablo Fededa, Christopher Esk, Beata Mierzwa, Rugile Stanyte, Shuiqiao Yuan, Huili Zheng, Klaus Ebnet, Wei Yan, Juergen A Knoblich, Daniel W Gerlich
Correct orientation of the mitotic spindle determines the plane of cellular cleavage and is crucial for organ development. In the developing cerebral cortex, spindle orientation defects result in severe neurodevelopmental disorders, but the precise mechanisms that control this important event are not fully understood. Here, we use a combination of high-content screening and mouse genetics to identify the miR-34/449 family as key regulators of mitotic spindle orientation in the developing cerebral cortex. By screening through all cortically expressed miRNAs in HeLa cells, we show that several members of the miR-34/449 family control mitotic duration and spindle rotation...
October 5, 2016: EMBO Journal
Pedro Vizán, Malte Beringer, Luciano Di Croce
No abstract text is available yet for this article.
October 4, 2016: EMBO Journal
Zuzana Storchová
No abstract text is available yet for this article.
September 28, 2016: EMBO Journal
Kenta Yamada, Koji Yamaguchi, Tomomi Shirakawa, Hirofumi Nakagami, Akira Mine, Kazuya Ishikawa, Masayuki Fujiwara, Mari Narusaka, Yoshihiro Narusaka, Kazuya Ichimura, Yuka Kobayashi, Hidenori Matsui, Yuko Nomura, Mika Nomoto, Yasuomi Tada, Yoichiro Fukao, Tamo Fukamizo, Kenichi Tsuda, Ken Shirasu, Naoto Shibuya, Tsutomu Kawasaki
Perception of microbe-associated molecular patterns by host cell surface pattern recognition receptors (PRRs) triggers the intracellular activation of mitogen-activated protein kinase (MAPK) cascades. However, it is not known how PRRs transmit immune signals to MAPK cascades in plants. Here, we identify a complete phospho-signaling transduction pathway from PRR-mediated pathogen recognition to MAPK activation in plants. We found that the receptor-like cytoplasmic kinase PBL27 connects the chitin receptor complex CERK1-LYK5 and a MAPK cascade...
September 27, 2016: EMBO Journal
Lars Bullinger
No abstract text is available yet for this article.
September 26, 2016: EMBO Journal
Bruno Antonny, Christopher Burd, Pietro De Camilli, Elizabeth Chen, Oliver Daumke, Katja Faelber, Marijn Ford, Vadim A Frolov, Adam Frost, Jenny E Hinshaw, Tom Kirchhausen, Michael M Kozlov, Martin Lenz, Harry H Low, Harvey McMahon, Christien Merrifield, Thomas D Pollard, Phillip J Robinson, Aurélien Roux, Sandra Schmid
The large GTPase dynamin is the first protein shown to catalyze membrane fission. Dynamin and its related proteins are essential to many cell functions, from endocytosis to organelle division and fusion, and it plays a critical role in many physiological functions such as synaptic transmission and muscle contraction. Research of the past three decades has focused on understanding how dynamin works. In this review, we present the basis for an emerging consensus on how dynamin functions. Three properties of dynamin are strongly supported by experimental data: first, dynamin oligomerizes into a helical polymer; second, dynamin oligomer constricts in the presence of GTP; and third, dynamin catalyzes membrane fission upon GTP hydrolysis...
September 26, 2016: EMBO Journal
Jiwon Hwang, Diedre Ribbens, Sumana Raychaudhuri, Leah Cairns, He Gu, Adam Frost, Siniša Urban, Peter J Espenshade
Hypoxic growth of fungi requires sterol regulatory element-binding protein (SREBP) transcription factors, and human opportunistic fungal pathogens require SREBP activation for virulence. Proteolytic release of fission yeast SREBPs from the membrane in response to low oxygen requires the Golgi membrane-anchored Dsc E3 ligase complex. Using genetic interaction arrays, we identified Rbd2 as a rhomboid family protease required for SREBP proteolytic processing. Rbd2 is an active, Golgi-localized protease that cleaves the transmembrane segment of the TatA rhomboid model substrate...
September 21, 2016: EMBO Journal
Elena Morelli, Valeria Mastrodonato, Galina V Beznoussenko, Alexandre A Mironov, Emiliana Tognon, Thomas Vaccari
The kinetochore is an essential structure that mediates accurate chromosome segregation in mitosis and meiosis. While many of the kinetochore components have been identified, the mechanisms of kinetochore assembly remain elusive. Here, we identify a novel role for Snap29, an unconventional SNARE, in promoting kinetochore assembly during mitosis in Drosophila and human cells. Snap29 localizes to the outer kinetochore and prevents chromosome mis-segregation and the formation of cells with fragmented nuclei. Snap29 promotes accurate chromosome segregation by mediating the recruitment of Knl1 at the kinetochore and ensuring stable microtubule attachments...
September 19, 2016: EMBO Journal
Dmytro Ustianenko, Josef Pasulka, Zuzana Feketova, Lukas Bednarik, Dagmar Zigackova, Andrea Fortova, Mihaela Zavolan, Stepanka Vanacova
Uridylation of various cellular RNA species at the 3' end has been generally linked to RNA degradation. In mammals, uridylated pre-let-7 miRNAs and mRNAs are targeted by the 3' to 5' exoribonuclease DIS3L2. Mutations in DIS3L2 have been associated with Perlman syndrome and with Wilms tumor susceptibility. Using in vivo cross-linking and immunoprecipitation (CLIP) method, we discovered the DIS3L2-dependent cytoplasmic uridylome of human cells. We found a broad spectrum of uridylated RNAs including rRNAs, snRNAs, snoRNAs, tRNAs, vault, 7SL, Y RNAs, mRNAs, lncRNAs, and transcripts from pseudogenes...
September 19, 2016: EMBO Journal
Martina Konantz, Elisa Alghisi, Joëlle S Müller, Anna Lenard, Virginie Esain, Kelli J Carroll, Lothar Kanz, Trista E North, Claudia Lengerke
During development, hematopoietic stem cells (HSCs) emerge from aortic endothelial cells (ECs) through an intermediate stage called hemogenic endothelium by a process known as endothelial-to-hematopoietic transition (EHT). While Notch signaling, including its upstream regulator Vegf, is known to regulate this process, the precise molecular control and temporal specificity of Notch activity remain unclear. Here, we identify the zebrafish transcriptional regulator evi1 as critically required for Notch-mediated EHT In vivo live imaging studies indicate that evi1 suppression impairs EC progression to hematopoietic fate and therefore HSC emergence...
September 16, 2016: EMBO Journal
Christoph Volkmann, Naema Brings, Martin Becker, Elias Hobeika, Jianying Yang, Michael Reth
How the B-cell antigen receptor (BCR) is activated upon interaction with its cognate antigen or with anti-BCR antibodies is not fully understood. We have recently shown that B-cell activation is accompanied by the opening of the pre-organized BCR oligomers, an observation that strengthens the role of receptor reorganization in signalling. We have now analysed the BCR oligomer opening and signalling upon treatment with different monovalent stimuli. Our results indicate that monovalent antigens are able to disturb and open the BCR oligomer, but that this requires the presence and activity of the Src family kinase (SFK) Lyn...
September 15, 2016: EMBO Journal
Aldwin Suryo Rahmanto, Vasil Savov, Andrä Brunner, Sara Bolin, Holger Weishaupt, Alena Malyukova, Gabriela Rosén, Matko Čančer, Sonja Hutter, Anders Sundström, Daisuke Kawauchi, David Tw Jones, Charles Spruck, Michael D Taylor, Yoon-Jae Cho, Stefan M Pfister, Marcel Kool, Andrey Korshunov, Fredrik J Swartling, Olle Sangfelt
SOX9 is a master transcription factor that regulates development and stem cell programs. However, its potential oncogenic activity and regulatory mechanisms that control SOX9 protein stability are poorly understood. Here, we show that SOX9 is a substrate of FBW7, a tumor suppressor, and a SCF (SKP1/CUL1/F-box)-type ubiquitin ligase. FBW7 recognizes a conserved degron surrounding threonine 236 (T236) in SOX9 that is phosphorylated by GSK3 kinase and consequently degraded by SCF(FBW) (7α) Failure to degrade SOX9 promotes migration, metastasis, and treatment resistance in medulloblastoma, one of the most common childhood brain tumors...
September 13, 2016: EMBO Journal
Benjamin M Schwenk, Hannelore Hartmann, Alperen Serdaroglu, Martin H Schludi, Daniel Hornburg, Felix Meissner, Denise Orozco, Alessio Colombo, Sabina Tahirovic, Meike Michaelsen, Franziska Schreiber, Simone Haupt, Michael Peitz, Oliver Brüstle, Clemens Küpper, Thomas Klopstock, Markus Otto, Albert C Ludolph, Thomas Arzberger, Peer-Hendrik Kuhn, Dieter Edbauer
Nuclear clearance of TDP-43 into cytoplasmic aggregates is a key driver of neurodegeneration in amyotrophic lateral sclerosis (ALS) and frontotemporal lobar degeneration (FTLD), but the mechanisms are unclear. Here, we show that TDP-43 knockdown specifically reduces the number and motility of RAB11-positive recycling endosomes in dendrites, while TDP-43 overexpression has the opposite effect. This is associated with delayed transferrin recycling in TDP-43-knockdown neurons and decreased β2-transferrin levels in patient CSF Whole proteome quantification identified the upregulation of the ESCRT component VPS4B upon TDP-43 knockdown in neurons...
September 12, 2016: EMBO Journal
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