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  • An optimized quantitative proteomics method establishes the cell type‐resolved mouse brain secretome
    EMBO J. (IF 9.889) Pub Date : 2020-09-21
    Johanna Tüshaus; Stephan A Müller; Evans Sioma Kataka; Jan Zaucha; Laura Sebastian Monasor; Minhui Su; Gökhan Güner; Georg Jocher; Sabina Tahirovic; Dmitrij Frishman; Mikael Simons; Stefan F Lichtenthaler

    To understand how cells communicate in the nervous system, it is essential to define their secretome, which is challenging for primary cells because of large cell numbers being required. Here, we miniaturized secretome analysis by developing the “high‐performance secretome protein enrichment with click sugars” (hiSPECS) method. To demonstrate its broad utility, hiSPECS was used to identify the secretory

    更新日期:2020-09-21
  • Long‐term expansion with germline potential of human primordial germ cell‐like cells in vitro
    EMBO J. (IF 9.889) Pub Date : 2020-09-20
    Yusuke Murase; Yukihiro Yabuta; Hiroshi Ohta; Chika Yamashiro; Tomonori Nakamura; Takuya Yamamoto; Mitinori Saitou

    Human germ cells perpetuate human genetic and epigenetic information. However, the underlying mechanism remains elusive, due to a lack of appropriate experimental systems. Here, we show that human primordial germ cell‐like cells (hPGCLCs) derived from human‐induced pluripotent stem cells (hiPSCs) can be propagated to at least ~106‐fold over a period of 4 months under a defined condition in vitro. During

    更新日期:2020-09-21
  • Novel features of centriole polarity and cartwheel stacking revealed by cryo‐tomography
    EMBO J. (IF 9.889) Pub Date : 2020-09-20
    Sergey Nazarov; Alexandra Bezler; Georgios N Hatzopoulos; Veronika Nemčíková Villímová; Davide Demurtas; Maeva Le Guennec; Paul Guichard; Pierre Gönczy

    Centrioles are polarized microtubule‐based organelles that seed the formation of cilia, and which assemble from a cartwheel containing stacked ring oligomers of SAS‐6 proteins. A cryo‐tomography map of centrioles from the termite flagellate Trichonympha spp. was obtained previously, but higher resolution analysis is likely to reveal novel features. Using sub‐tomogram averaging (STA) in T. spp. and

    更新日期:2020-09-21
  • Architecture of the centriole cartwheel‐containing region revealed by cryo‐electron tomography
    EMBO J. (IF 9.889) Pub Date : 2020-09-20
    Nikolai Klena; Maeva Le Guennec; Anne‐Marie Tassin; Hugo van den Hoek; Philipp S Erdmann; Miroslava Schaffer; Stefan Geimer; Gabriel Aeschlimann; Lubomir Kovacik; Yashar Sadian; Kenneth N Goldie; Henning Stahlberg; Benjamin D Engel; Virginie Hamel; Paul Guichard

    Centrioles are evolutionarily conserved barrels of microtubule triplets that form the core of the centrosome and the base of the cilium. While the crucial role of the proximal region in centriole biogenesis has been well documented, its native architecture and evolutionary conservation remain relatively unexplored. Here, using cryo‐electron tomography of centrioles from four evolutionarily distant

    更新日期:2020-09-21
  • Structural basis for the activation and suppression of transposition during evolution of the RAG recombinase
    EMBO J. (IF 9.889) Pub Date : 2020-09-18
    Yuhang Zhang; Elizabeth Corbett; Shenping Wu; David G Schatz

    Jawed vertebrate adaptive immunity relies on the RAG1/RAG2 (RAG) recombinase, a domesticated transposase, for assembly of antigen receptor genes. Using an integration‐activated form of RAG1 with methionine at residue 848 and cryo‐electron microscopy, we determined structures that capture RAG engaged with transposon ends and U‐shaped target DNA prior to integration (the target capture complex) and two

    更新日期:2020-09-20
  • Reprogrammed mRNA translation drives resistance to therapeutic targeting of ribosome biogenesis
    EMBO J. (IF 9.889) Pub Date : 2020-09-18
    Eric P Kusnadi; Anna S Trigos; Carleen Cullinane; David L Goode; Ola Larsson; Jennifer R Devlin; Keefe T Chan; David P De Souza; Malcolm J McConville; Grant A McArthur; George Thomas; Elaine Sanij; Gretchen Poortinga; Ross D Hannan; Katherine M Hannan; Jian Kang; Richard B Pearson

    Elevated ribosome biogenesis in oncogene‐driven cancers is commonly targeted by DNA‐damaging cytotoxic drugs. Our previous first‐in‐human trial of CX‐5461, a novel, less genotoxic agent that specifically inhibits ribosome biogenesis via suppression of RNA polymerase I (Pol I) transcription, revealed single‐agent efficacy in refractory blood cancers. Despite this clinical response, patients were not

    更新日期:2020-09-20
  • A genetic memory initiates the epigenetic loop necessary to preserve centromere position
    EMBO J. (IF 9.889) Pub Date : 2020-09-18
    Sebastian Hoffmann; Helena M Izquierdo; Riccardo Gamba; Florian Chardon; Marie Dumont; Veer Keizer; Solène Hervé; Shannon M McNulty; Beth A Sullivan; Nicolas Manel; Daniele Fachinetti

    Centromeres are built on repetitive DNA sequences (CenDNA) and a specific chromatin enriched with the histone H3 variant CENP‐A, the epigenetic mark that identifies centromere position. Here, we interrogate the importance of CenDNA in centromere specification by developing a system to rapidly remove and reactivate CENP‐A (CENP‐AOFF/ON). Using this system, we define the temporal cascade of events necessary

    更新日期:2020-09-20
  • RNA localization and co‐translational interactions control RAB13 GTPase function and cell migration
    EMBO J. (IF 9.889) Pub Date : 2020-09-18
    Konstadinos Moissoglu; Michael Stueland; Alexander N Gasparski; Tianhong Wang; Lisa M Jenkins; Michelle L Hastings; Stavroula Mili

    Numerous RNAs exhibit specific distribution patterns in mammalian cells. However, the functional and mechanistic consequences are relatively unknown. Here, we investigate the functional role of RNA localization at cellular protrusions of migrating mesenchymal cells, using as a model the RAB13 RNA, which encodes a GTPase important for vesicle‐mediated membrane trafficking. While RAB13 RNA is enriched

    更新日期:2020-09-20
  • RAB13 mRNA compartmentalisation spatially orients tissue morphogenesis
    EMBO J. (IF 9.889) Pub Date : 2020-09-18
    Guilherme Costa; Joshua J Bradbury; Nawseen Tarannum; Shane P Herbert

    Polarised targeting of diverse mRNAs to cellular protrusions is a hallmark of cell migration. Although a widespread phenomenon, definitive functions for endogenous targeted mRNAs and their relevance to modulation of in vivo tissue dynamics remain elusive. Here, using single‐molecule analysis, gene editing and zebrafish live‐cell imaging, we report that mRNA polarisation acts as a molecular compass

    更新日期:2020-09-20
  • Clustering of strong replicators associated with active promoters is sufficient to establish an early‐replicating domain
    EMBO J. (IF 9.889) Pub Date : 2020-09-16
    Caroline Brossas; Anne‐Laure Valton; Sergey V Venev; Sabarinadh Chilaka; Antonin Counillon; Marc Laurent; Coralie Goncalves; Bénédicte Duriez; Franck Picard; Job Dekker; Marie‐Noëlle Prioleau

    Vertebrate genomes replicate according to a precise temporal program strongly correlated with their organization into A/B compartments. Until now, the molecular mechanisms underlying the establishment of early‐replicating domains remain largely unknown. We defined two minimal cis‐element modules containing a strong replication origin and chromatin modifier binding sites capable of shifting a targeted

    更新日期:2020-09-16
  • Re‐equilibration of imbalanced NAD metabolism ameliorates the impact of telomere dysfunction
    EMBO J. (IF 9.889) Pub Date : 2020-09-16
    Chongkui Sun; Kun Wang; Amanda J Stock; Yi Gong; Tyler G Demarest; Beimeng Yang; Neelam Giri; Lea Harrington; Blanche P Alter; Sharon A Savage; Vilhelm A Bohr; Yie Liu

    Short telomeres are a principal defining feature of telomere biology disorders, such as dyskeratosis congenita (DC), for which there are no effective treatments. Here, we report that primary fibroblasts from DC patients and late generation telomerase knockout mice display lower nicotinamide adenine dinucleotide (NAD) levels, and an imbalance in the NAD metabolome that includes elevated CD38 NADase

    更新日期:2020-09-16
  • MSH2 shapes the meiotic crossover landscape in relation to interhomolog polymorphism in Arabidopsis
    EMBO J. (IF 9.889) Pub Date : 2020-09-16
    Alexander R Blackwell; Julia Dluzewska; Maja Szymanska‐Lejman; Stuart Desjardins; Andrew J Tock; Nadia Kbiri; Christophe Lambing; Emma J Lawrence; Tomasz Bieluszewski; Beth Rowan; James D Higgins; Piotr A Ziolkowski; Ian R Henderson

    During meiosis, DNA double‐strand breaks undergo interhomolog repair to yield crossovers between homologous chromosomes. To investigate how interhomolog sequence polymorphism affects crossovers, we sequenced multiple recombinant populations of the model plant Arabidopsis thaliana. Crossovers were elevated in the diverse pericentromeric regions, showing a local preference for polymorphic regions. We

    更新日期:2020-09-16
  • Negative regulation of NEMO signaling by the ubiquitin E3 ligase MARCH2
    EMBO J. (IF 9.889) Pub Date : 2020-09-16
    Kiramage Chathuranga; Tae‐Hwan Kim; Hyuncheol Lee; Jun‐Seol Park; Jae‐Hoon Kim; Wijesinghe A Gayan Chathuranga; Pathum Ekanayaka; Youn Jung Choi; Chul‐Ho Lee; Chul‐Joong Kim; Jae U Jung; Jong‐Soo Lee

    NF‐κB essential modulator (NEMO) is a key regulatory protein that functions during NF‐κB‐ and interferon‐mediated signaling in response to extracellular stimuli and pathogen infections. Tight regulation of NEMO is essential for host innate immune responses and for maintenance of homeostasis. Here, we report that the E3 ligase MARCH2 is a novel negative regulator of NEMO‐mediated signaling upon bacterial

    更新日期:2020-09-16
  • β‐catenin signaling modulates the tempo of dendritic growth of adult‐born hippocampal neurons
    EMBO J. (IF 9.889) Pub Date : 2020-09-15
    Jana Heppt; Marie‐Theres Wittmann; Iris Schäffner; Charlotte Billmann; Jingzhong Zhang; Daniela Vogt‐Weisenhorn; Nilima Prakash; Wolfgang Wurst; Makoto Mark Taketo; Dieter Chichung Lie

    In adult hippocampal neurogenesis, stem/progenitor cells generate dentate granule neurons that contribute to hippocampal plasticity. The establishment of a morphologically defined dendritic arbor is central to the functional integration of adult‐born neurons. We investigated the role of canonical Wnt/β‐catenin signaling in dendritogenesis of adult‐born neurons. We show that canonical Wnt signaling

    更新日期:2020-09-15
  • IL‐2/IL‐7‐inducible factors pioneer the path to T cell differentiation in advance of lineage‐defining factors
    EMBO J. (IF 9.889) Pub Date : 2020-09-15
    Sarah L Bevington; Peter Keane; Jake K Soley; Saskia Tauch; Dominika W Gajdasik; Remi Fiancette; Veronika Matei‐Rascu; Claire M Willis; David R Withers; Peter N Cockerill

    When dormant naïve T cells first become activated by antigen‐presenting cells, they express the autocrine growth factor IL‐2 which transforms them into rapidly dividing effector T cells. During this process, hundreds of genes undergo epigenetic reprogramming for efficient activation, and also for potential reactivation after they return to quiescence as memory T cells. However, the relative contributions

    更新日期:2020-09-15
  • LRRK2 to the rescue of damaged endomembranes.
    EMBO J. (IF 9.889) Pub Date : 2020-08-16
    Maja Radulovic,Harald Stenmark

    Mutations in several genes encoding for lysosomal proteins are involved in Parkinson's disease (PD). In this issue, Herbst et al (2020) show that PD‐related leucine‐rich repeat kinase 2 (LRRK2) is activated in response to pathogen or membranolytic drug‐induced damage of phagolysosomes and lysosomes in macrophages, and regulates endolysosomal homeostasis by controlling the balance between membrane repair

    更新日期:2020-09-15
  • A Timeless Tale: G4 structure recognition by the fork protection complex triggers unwinding by DDX11 helicase.
    EMBO J. (IF 9.889) Pub Date : 2020-08-13
    Catherine H Freudenreich

    How the replisome senses and deals with DNA secondary structures has been a mystery. A new study from the Sale and Pellegrini laboratories finds that the Timeless protein has a G‐quadruplex binding domain that works together with the DDX11 helicase to facilitate replication of G4 DNA structures.

    更新日期:2020-09-15
  • A hairy tale: SIRT7 safeguards skin stem cells during aging.
    EMBO J. (IF 9.889) Pub Date : 2020-08-16
    Matthew Simon,Stephan Emmrich,Andrei Seluanov,Vera Gorbunova

    Stem cell regulation during both normal development and aging has become one of the fastest growing topics in biology. Here, new work by Li et al (2020) offers insight into the aging process within epithelial skin stem cells and highlights how SIRT7, a member of the sirtuin family of protein deacylases and mono‐ADP ribosylases, protects adult hair follicle stem cells from aging by ensuring their hair

    更新日期:2020-09-15
  • LRRK2 activation controls the repair of damaged endomembranes in macrophages.
    EMBO J. (IF 9.889) Pub Date : 2020-07-09
    Susanne Herbst,Philip Campbell,John Harvey,Elliott M Bernard,Venizelos Papayannopoulos,Nicholas W Wood,Huw R Morris,Maximiliano G Gutierrez

    Cells respond to endolysosome damage by either repairing the damage or targeting damaged endolysosomes for degradation via lysophagy. However, the signals regulating the decision for repair or lysophagy are poorly characterised. Here, we show that the Parkinson's disease (PD)‐related kinase LRRK2 is activated in macrophages by pathogen‐ or sterile‐induced endomembrane damage. LRRK2 recruits the Rab

    更新日期:2020-09-15
  • Timeless couples G-quadruplex detection with processing by DDX11 helicase during DNA replication.
    EMBO J. (IF 9.889) Pub Date : 2020-07-23
    Leticia K Lerner,Sandro Holzer,Mairi L Kilkenny,Saša Šviković,Pierre Murat,Davide Schiavone,Cara B Eldridge,Alice Bittleston,Joseph D Maman,Dana Branzei,Katherine Stott,Luca Pellegrini,Julian E Sale

    Regions of the genome with the potential to form secondary DNA structures pose a frequent and significant impediment to DNA replication and must be actively managed in order to preserve genetic and epigenetic integrity. How the replisome detects and responds to secondary structures is poorly understood. Here, we show that a core component of the fork protection complex in the eukaryotic replisome,

    更新日期:2020-09-15
  • SIRT7 activates quiescent hair follicle stem cells to ensure hair growth in mice.
    EMBO J. (IF 9.889) Pub Date : 2020-07-21
    Guo Li,Xiaolong Tang,Shuping Zhang,Meiling Jin,Ming Wang,Zhili Deng,Zuojun Liu,Minxian Qian,Wei Shi,Zimei Wang,Hongfu Xie,Ji Li,Baohua Liu

    Hair follicle stem cells (HFSCs) are maintained in a quiescent state until activated to grow, but the mechanisms that reactivate the quiescent HFSC reservoir are unclear. Here, we find that loss of Sirt7 in mice impedes hair follicle life‐cycle transition from telogen to anagen phase, resulting in delay of hair growth. Conversely, Sirt7 overexpression during telogen phase facilitated HSFC anagen entry

    更新日期:2020-09-15
  • Mechanism and inhibition of the papain‐like protease, PLpro, of SARS‐CoV‐2
    EMBO J. (IF 9.889) Pub Date : 2020-08-26
    Theresa Klemm; Gregor Ebert; Dale J Calleja; Cody C Allison; Lachlan W Richardson; Jonathan P Bernardini; Bernadine GC Lu; Nathan W Kuchel; Christoph Grohmann; Yuri Shibata; Zhong Yan Gan; James P Cooney; Marcel Doerflinger; Amanda E Au; Timothy R Blackmore; Gerbrand J van der Heden van Noort; Paul P Geurink; Huib Ovaa; Janet Newman; Alan Riboldi‐Tunnicliffe; Peter E Czabotar; Jeffrey P Mitchell; Rebecca

    The SARS‐CoV‐2 coronavirus encodes an essential papain‐like protease domain as part of its non‐structural protein (nsp)‐3, namely SARS2 PLpro, that cleaves the viral polyprotein, but also removes ubiquitin‐like ISG15 protein modifications as well as, with lower activity, Lys48‐linked polyubiquitin. Structures of PLpro bound to ubiquitin and ISG15 reveal that the S1 ubiquitin‐binding site is responsible

    更新日期:2020-09-15
  • Open conformation of tetraspanins shapes interaction partner networks on cell membranes
    EMBO J. (IF 9.889) Pub Date : 2020-08-16
    Yihu Yang; Xiaoran Roger Liu; Zev J Greenberg; Fengbo Zhou; Peng He; Lingling Fan; Shixuan Liu; Guomin Shen; Takeshi Egawa; Michael L Gross; Laura G Schuettpelz; Weikai Li

    Tetraspanins, including CD53 and CD81, regulate a multitude of cellular processes through organizing an interaction network on cell membranes. Here, we report the crystal structure of CD53 in an open conformation poised for partner interaction. The large extracellular domain (EC2) of CD53 protrudes away from the membrane surface and exposes a variable region, which is identified by hydrogen–deuterium

    更新日期:2020-09-15
  • Complex IV subunit isoform COX6A2 protects fast-spiking interneurons from oxidative stress and supports their function.
    EMBO J. (IF 9.889) Pub Date : 2020-08-03
    Berta Sanz-Morello,Ulrich Pfisterer,Nikolaj Winther Hansen,Samuel Demharter,Ashish Thakur,Katsunori Fujii,Sergey A Levitskii,Alexia Montalant,Irina Korshunova,Pradeep Pa Mammen,Piotr Kamenski,Satoru Noguchi,Blanca Irene Aldana,Karin Sørig Hougaard,Jean-François Perrier,Konstantin Khodosevich

    Parvalbumin‐positive (PV+) fast‐spiking interneurons are essential to control the firing activity of principal neuron ensembles, thereby regulating cognitive processes. The high firing frequency activity of PV+ interneurons imposes high‐energy demands on their metabolism that must be supplied by distinctive machinery for energy generation. Exploring single‐cell transcriptomic data for the mouse cortex

    更新日期:2020-09-15
  • Prevention of dsRNA-induced interferon signaling by AGO1x is linked to breast cancer cell proliferation.
    EMBO J. (IF 9.889) Pub Date : 2020-08-19
    Souvik Ghosh,Joao C Guimaraes,Manuela Lanzafame,Alexander Schmidt,Afzal Pasha Syed,Beatrice Dimitriades,Anastasiya Börsch,Shreemoyee Ghosh,Nitish Mittal,Thomas Montavon,Ana Luisa Correia,Johannes Danner,Gunter Meister,Luigi M Terracciano,Sébastien Pfeffer,Salvatore Piscuoglio,Mihaela Zavolan

    Translational readthrough, i.e., elongation of polypeptide chains beyond the stop codon, was initially reported for viral RNA, but later found also on eukaryotic transcripts, resulting in proteome diversification and protein‐level modulation. Here, we report that AGO1x, an evolutionarily conserved translational readthrough isoform of Argonaute 1, is generated in highly proliferative breast cancer cells

    更新日期:2020-09-15
  • RNF43 truncations trap CK1 to drive niche‐independent self‐renewal in cancer
    EMBO J. (IF 9.889) Pub Date : 2020-08-10
    Maureen Spit; Nicola Fenderico; Ingrid Jordens; Tomasz Radaszkiewicz; Rik GH Lindeboom; Jeroen M Bugter; Alba Cristobal; Lars Ootes; Max van Osch; Eline Janssen; Kim E Boonekamp; Katerina Hanakova; David Potesil; Zbynek Zdrahal; Sylvia F Boj; Jan Paul Medema; Vitezslav Bryja; Bon‐Kyoung Koo; Michiel Vermeulen; Madelon M Maurice

    Wnt/β‐catenin signaling is a primary pathway for stem cell maintenance during tissue renewal and a frequent target for mutations in cancer. Impaired Wnt receptor endocytosis due to loss of the ubiquitin ligase RNF43 gives rise to Wnt‐hypersensitive tumors that are susceptible to anti‐Wnt‐based therapy. Contrary to this paradigm, we identify a class of RNF43 truncating cancer mutations that induce β‐catenin‐mediated

    更新日期:2020-09-15
  • The tRNA pseudouridine synthase TruB1 regulates the maturation of let‐7 miRNA
    EMBO J. (IF 9.889) Pub Date : 2020-09-14
    Ryota Kurimoto; Tomoki Chiba; Yoshiaki Ito; Takahide Matsushima; Yuki Yano; Kohei Miyata; Yuka Yashiro; Tsutomu Suzuki; Kozo Tomita; Hiroshi Asahara

    Let‐7 is an evolutionary conserved microRNA that mediates post‐transcriptional gene silencing to regulate a wide range of biological processes, including development, differentiation, and tumor suppression. Let‐7 biogenesis is tightly regulated by several RNA‐binding proteins, including Lin28A/B, which represses let‐7 maturation. To identify new regulators of let‐7, we devised a cell‐based functional

    更新日期:2020-09-14
  • SEUSS integrates transcriptional and epigenetic control of root stem cell organizer specification
    EMBO J. (IF 9.889) Pub Date : 2020-09-14
    Huawei Zhai; Xiaoyue Zhang; Yanrong You; Lihao Lin; Wenkun Zhou; Chuanyou Li

    Proper regulation of homeotic gene expression is critical for stem cell fate in both plants and animals. In Arabidopsis thaliana, the WUSCHEL (WUS)‐RELATED HOMEOBOX 5 (WOX5) gene is specifically expressed in a group of root stem cell organizer cells called the quiescent center (QC) and plays a central role in QC specification. Here, we report that the SEUSS (SEU) protein, homologous to the animal LIM‐domain

    更新日期:2020-09-14
  • EGFR‐mediated tyrosine phosphorylation of STING determines its trafficking route and cellular innate immunity functions
    EMBO J. (IF 9.889) Pub Date : 2020-09-14
    Chenyao Wang; Xin Wang; Manoj Veleeparambil; Patricia M Kessler; Belinda Willard; Saurabh Chattopadhyay; Ganes C Sen

    STING (STimulator of INterferon Genes) mediates protective cellular response to microbial infection and tissue damage, but its aberrant activation can lead to autoinflammatory diseases. Upon ligand stimulation, the endoplasmic reticulum (ER) protein STING translocates to endosomes for induction of interferon production, while an alternate trafficking route delivers it directly to the autophagosomes

    更新日期:2020-09-14
  • FRX proteins bring new perspectives to nucleoporins' homeostasis
    EMBO J. (IF 9.889) Pub Date : 2020-09-11
    Guillaume Holzer; Wolfram Antonin

    FXR proteins are part of ribonucleoprotein granules controlling stability, translation, and cellular localization of target mRNAs. In the current issue, Agote‐Aran et al extend the repertoire of FXR protein action and show that they are also involved in the transport of nuclear pore complex components to the nuclear envelope and thereby prevent cytoplasmic aggregation of these proteins.

    更新日期:2020-09-11
  • Structures of the SARS‐CoV‐2 nucleocapsid and their perspectives for drug design
    EMBO J. (IF 9.889) Pub Date : 2020-09-11
    Ya Peng; Ning Du; Yuqing Lei; Sonam Dorje; Jianxun Qi; Tingrong Luo; George F Gao; Hao Song

    COVID‐19, caused by SARS‐CoV‐2, has resulted in severe and unprecedented economic and social disruptions in the world. Nucleocapsid (N) protein, which is the major structural component of the virion and is involved in viral replication, assembly and immune regulation, plays key roles in the viral life cycle. Here, we solved the crystal structures of the N‐ and C‐terminal domains (N‐NTD and N‐CTD) of

    更新日期:2020-09-11
  • Siwi levels reversibly regulate secondary piRISC biogenesis by affecting Ago3 body morphology in Bombyx mori
    EMBO J. (IF 9.889) Pub Date : 2020-09-11
    Kazumichi M Nishida; Kazuhiro Sakakibara; Tetsutaro Sumiyoshi; Hiroya Yamazaki; Taro Mannen; Takeshi Kawamura; Tatsuhiko Kodama; Mikiko C Siomi

    Silkworm ovarian germ cells produce the Siwi‐piRNA‐induced silencing complex (piRISC) through two consecutive mechanisms, the primary pathway and the secondary ping‐pong cycle. Primary Siwi‐piRISC production occurs on the outer mitochondrial membrane in an Ago3‐independent manner, where Tudor domain‐containing Papi binds unloaded Siwi via its symmetrical dimethylarginines (sDMAs). Here, we now show

    更新日期:2020-09-11
  • A map of human breast cancer: new players in stromal‐immune crosstalk
    EMBO J. (IF 9.889) Pub Date : 2020-09-10
    Kathleen M McAndrews; Raghu Kalluri

    Prominent accumulation of mesenchymal cells within tumors has long been appreciated, and recent studies suggest molecular and functional diversity of stromal components. In this issue, Wu et al (2020) employed single‐cell RNA sequencing of primary human breast tumors and identified new subsets of stromal mesenchymal cells with distinct transcriptional profiles, tissue localization, and associative

    更新日期:2020-09-10
  • Molecular basis for the bifunctional Uba4–Urm1 sulfur‐relay system in tRNA thiolation and ubiquitin‐like conjugation
    EMBO J. (IF 9.889) Pub Date : 2020-09-09
    Marta Pabis; Martin Termathe; Keerthiraju E Ravichandran; Sandra D Kienast; Rościsław Krutyhołowa; Mikołaj Sokołowski; Urszula Jankowska; Przemysław Grudnik; Sebastian A Leidel; Sebastian Glatt

    The chemical modification of tRNA bases by sulfur is crucial to tune translation and to optimize protein synthesis. In eukaryotes, the ubiquitin‐related modifier 1 (Urm1) pathway is responsible for the synthesis of 2‐thiolated wobble uridine (U34). During the key step of the modification cascade, the E1‐like activating enzyme ubiquitin‐like protein activator 4 (Uba4) first adenylates and thiocarboxylates

    更新日期:2020-09-10
  • HIV‐1 capsids mimic a microtubule regulator to coordinate early stages of infection
    EMBO J. (IF 9.889) Pub Date : 2020-09-08
    Eveline Santos da Silva; Shanmugapriya Shanmugapriya; Viacheslav Malikov; Feng Gu; M Keegan Delaney; Mojgan H Naghavi

    While the microtubule end‐binding protein, EB1 facilitates early stages of HIV‐1 infection, how it does so remains unclear. Here, we show that beyond its effects on microtubule acetylation, EB1 also indirectly contributes to infection by delivering the plus‐end tracking protein (+TIP), cytoplasmic linker protein 170 (CLIP170) to the cell periphery. CLIP170 bound to intact HIV‐1 cores or in vitro assembled

    更新日期:2020-09-08
  • Fxr1 regulates sleep and synaptic homeostasis.
    EMBO J. (IF 9.889) Pub Date : 2020-09-07
    Jivan Khlghatyan,Alesya Evstratova,Lusine Bozoyan,Simon Chamberland,Dipashree Chatterjee,Aleksandra Marakhovskaia,Tiago Soares Silva,Katalin Toth,Valerie Mongrain,Jean-Martin Beaulieu

    The fragile X autosomal homolog 1 (Fxr1) is regulated by lithium and has been GWAS‐associated with schizophrenia and insomnia. Homeostatic regulation of synaptic strength is essential for the maintenance of brain functions and involves both cell‐autonomous and system‐level processes such as sleep. We examined the contribution of Fxr1 to cell‐autonomous homeostatic synaptic scaling and neuronal responses

    更新日期:2020-09-08
  • Thinking "ethical" when designing an international, cross-disciplinary biomedical research consortium.
    EMBO J. (IF 9.889) Pub Date : 2020-09-07
    Maria-Elena Torres-Padilla,Annelien L Bredenoord,Karin R Jongsma,Astrid Lunkes,Luca Marelli,Ines Pinheiro,Giuseppe Testa

    This commentary outlines challenges with identifying and implementing ethical, legal and societal considerations when initiating large-scale scientific programs and suggests best practices to ensure responsible research.

    更新日期:2020-09-07
  • A metabolite binding protein moonlights as a bile-responsive chaperone.
    EMBO J. (IF 9.889) Pub Date : 2020-09-03
    Changhan Lee,Patrick Betschinger,Kevin Wu,Dawid S Żyła,Rudi Glockshuber,James Ca Bardwell

    Bile salts are secreted into the gastrointestinal tract to aid in the absorption of lipids. In addition, bile salts show potent antimicrobial activity in part by mediating bacterial protein unfolding and aggregation. Here, using a protein folding sensor, we made the surprising discovery that the Escherichia coli periplasmic glycerol‐3‐phosphate (G3P)‐binding protein UgpB can serve, in the absence of

    更新日期:2020-09-03
  • SARS-CoV-2 targets neurons of 3D human brain organoids.
    EMBO J. (IF 9.889) Pub Date : 2020-09-02
    Anand Ramani,Lisa Müller,Philipp Niklas Ostermann,Elke Gabriel,Pranty Abida-Islam,Andreas Müller-Schiffmann,Aruljothi Mariappan,Olivier Goureau,Henning Gruell,Andreas Walker,Marcel Andrée,Sandra Hauka,Torsten Houwaart,Alexander Dilthey,Kai Wohlgemuth,Heymut Omran,Florian Klein,Dagmar Wieczorek,Ortwin Adams,Jörg Timm,Carsten Korth,Heiner Schaal,Jay Gopalakrishnan

    COVID-19 pandemic caused by SARS-CoV-2 infection is a public health emergency. COVID-19 typically exhibits respiratory illness. Unexpectedly, emerging clinical reports indicate that neurological symptoms continue to rise, suggesting detrimental effects of SARS-CoV-2 on the central nervous system (CNS). Here, we show that a Düsseldorf isolate of SARS-CoV-2 enters 3D human brain organoids within two

    更新日期:2020-09-02
  • Ending on a high note: Downstream ORFs enhance mRNA translational output.
    EMBO J. (IF 9.889) Pub Date : 2020-08-03
    Samantha Dodbele,Jeremy E Wilusz

    Eukaryotic mRNAs were long thought to only translate a single protein product, but it is now recognized that many mRNAs can also encode small open reading frames (ORFs). In this issue of The EMBO Journal, Wu et al characterized small ORFs in the 3′ untranslated regions (3′ UTRs) of human and zebrafish mRNAs and found that many are indeed translated. The peptides encoded by these downstream ORFs (dORFs)

    更新日期:2020-09-01
  • Selective autophagy bears bone.
    EMBO J. (IF 9.889) Pub Date : 2020-07-27
    Milana Fraiberg,Zvulun Elazar

    The endoplasmic reticulum (ER) is a dynamic intracellular network responsible for folding and maturation of organellar and secreted proteins. Selective autophagy of ER (ER‐phagy) is emerging as an essential process that maintains proteostasis in the ER and is regulated by growth conditions. In this issue, Cinque et al (2020) show that fibroblast growth factor 18 (FGF18) specifically activates ER‐phagy

    更新日期:2020-09-01
  • Manipulation of epithelial cell death pathways by Shigella.
    EMBO J. (IF 9.889) Pub Date : 2020-08-10
    Sara J Thygesen,Adriana Pliego-Zamora,Katryn J Stacey

    Shigella, a major cause of bacterial dysentery, knows when it is not wanted. To generate and maintain its niche within host cells, this unwelcome guest injects several dozen virulence factors via a type 3 secretion system (T3SS). In this issue, Ashida et al (2020) have elucidated the role of two such factors from Shigella flexneri—OspC1 and OspD3—that together counteract apoptotic and necroptotic death

    更新日期:2020-09-01
  • Translation of small downstream ORFs enhances translation of canonical main open reading frames.
    EMBO J. (IF 9.889) Pub Date : 2020-08-03
    Qiushuang Wu,Matthew Wright,Madelaine M Gogol,William D Bradford,Ning Zhang,Ariel A Bazzini

    In addition to canonical open reading frames (ORFs), thousands of translated small ORFs (containing less than 100 codons) have been identified in untranslated mRNA regions (UTRs) across eukaryotes. Small ORFs in 5′ UTRs (upstream (u)ORFs) often repress translation of the canonical ORF within the same mRNA. However, the function of translated small ORFs in the 3′ UTRs (downstream (d)ORFs) is unknown

    更新日期:2020-09-01
  • MiT/TFE factors control ER-phagy via transcriptional regulation of FAM134B.
    EMBO J. (IF 9.889) Pub Date : 2020-07-27
    Laura Cinque,Chiara De Leonibus,Maria Iavazzo,Natalie Krahmer,Daniela Intartaglia,Francesco Giuseppe Salierno,Rossella De Cegli,Chiara Di Malta,Maria Svelto,Carmela Lanzara,Marianna Maddaluno,Luca Giorgio Wanderlingh,Antje K Huebner,Marcella Cesana,Florian Bonn,Elena Polishchuk,Christian A Hübner,Ivan Conte,Ivan Dikic,Matthias Mann,Andrea Ballabio,Francesca Sacco,Paolo Grumati,Carmine Settembre

    Lysosomal degradation of the endoplasmic reticulum (ER) via autophagy (ER‐phagy) is emerging as a critical regulator of cell homeostasis and function. The recent identification of ER‐phagy receptors has shed light on the molecular mechanisms underlining this process. However, the signaling pathways regulating ER‐phagy in response to cellular needs are still largely unknown. We found that the nutrient

    更新日期:2020-09-01
  • A unique bacterial tactic to circumvent the cell death crosstalk induced by blockade of caspase-8.
    EMBO J. (IF 9.889) Pub Date : 2020-07-13
    Hiroshi Ashida,Chihiro Sasakawa,Toshihiko Suzuki

    Upon invasive bacterial infection of colonic epithelium, host cells induce several types of cell death to eliminate pathogens. For instance, necroptosis is a RIPK‐dependent lytic cell death that serves as a backup system to fully eliminate intracellular pathogens when apoptosis is inhibited; this phenomenon has been termed “cell death crosstalk”. To maintain their replicative niche and multiply within

    更新日期:2020-09-01
  • ADAM17-triggered TNF signalling protects the ageing Drosophila retina from lipid droplet-mediated degeneration.
    EMBO J. (IF 9.889) Pub Date : 2020-07-26
    Sonia Muliyil,Clémence Levet,Stefan Düsterhöft,Iqbal Dulloo,Sally A Cowley,Matthew Freeman

    Animals have evolved multiple mechanisms to protect themselves from the cumulative effects of age‐related cellular damage. Here, we reveal an unexpected link between the TNF (tumour necrosis factor) inflammatory pathway, triggered by the metalloprotease ADAM17/TACE, and a lipid droplet (LD)‐mediated mechanism of protecting retinal cells from age‐related degeneration. Loss of ADAM17, TNF and the TNF

    更新日期:2020-09-01
  • Phytohormone cytokinin guides microtubule dynamics during cell progression from proliferative to differentiated stage.
    EMBO J. (IF 9.889) Pub Date : 2020-07-15
    Juan Carlos Montesinos,Anas Abuzeineh,Aglaja Kopf,Alba Juanes-Garcia,Krisztina Ötvös,Jan Petrášek,Michael Sixt,Eva Benková

    Cell production and differentiation for the acquisition of specific functions are key features of living systems. The dynamic network of cellular microtubules provides the necessary platform to accommodate processes associated with the transition of cells through the individual phases of cytogenesis. Here, we show that the plant hormone cytokinin fine‐tunes the activity of the microtubular cytoskeleton

    更新日期:2020-09-01
  • Genome-wide cooperation of EMT transcription factor ZEB1 with YAP and AP-1 in breast cancer.
    EMBO J. (IF 9.889) Pub Date : 2020-07-21
    Nora Feldker,Fulvia Ferrazzi,Harald Schuhwerk,Sebastian A Widholz,Kerstin Guenther,Isabell Frisch,Kathrin Jakob,Julia Kleemann,Dania Riegel,Ulrike Bönisch,Sören Lukassen,Rebecca L Eccles,Christian Schmidl,Marc P Stemmler,Thomas Brabletz,Simone Brabletz

    Invasion, metastasis and therapy resistance are the major cause of cancer‐associated deaths, and the EMT‐inducing transcription factor ZEB1 is a crucial stimulator of these processes. While work on ZEB1 has mainly focused on its role as a transcriptional repressor, it can also act as a transcriptional activator. To further understand these two modes of action, we performed a genome‐wide ZEB1 binding

    更新日期:2020-09-01
  • Systematic analysis of the IL-17 receptor signalosome reveals a robust regulatory feedback loop.
    EMBO J. (IF 9.889) Pub Date : 2020-07-21
    Helena Draberova,Sarka Janusova,Daniela Knizkova,Tereza Semberova,Michaela Pribikova,Andrea Ujevic,Karel Harant,Sofija Knapkova,Matous Hrdinka,Viola Fanfani,Giovanni Stracquadanio,Ales Drobek,Klara Ruppova,Ondrej Stepanek,Peter Draber

    IL‐17 mediates immune protection from fungi and bacteria, as well as it promotes autoimmune pathologies. However, the regulation of the signal transduction from the IL‐17 receptor (IL‐17R) remained elusive. We developed a novel mass spectrometry‐based approach to identify components of the IL‐17R complex followed by analysis of their roles using reverse genetics. Besides the identification of linear

    更新日期:2020-09-01
  • TBK1 phosphorylates mutant Huntingtin and suppresses its aggregation and toxicity in Huntington's disease models.
    EMBO J. (IF 9.889) Pub Date : 2020-08-05
    Ramanath Narayana Hegde,Anass Chiki,Lara Petricca,Paola Martufi,Nicolas Arbez,Laurent Mouchiroud,Johan Auwerx,Christian Landles,Gillian P Bates,Malvindar K Singh-Bains,Mike Dragunow,Maurice A Curtis,Richard Lm Faull,Christopher A Ross,Andrea Caricasole,Hilal A Lashuel

    Phosphorylation of the N‐terminal domain of the huntingtin (HTT) protein has emerged as an important regulator of its localization, structure, aggregation, clearance and toxicity. However, validation of the effect of bona fide phosphorylation in vivo and assessing the therapeutic potential of targeting phosphorylation for the treatment of Huntington's disease (HD) require the identification of the

    更新日期:2020-09-01
  • A small targeting domain in Ty1 integrase is sufficient to direct retrotransposon integration upstream of tRNA genes.
    EMBO J. (IF 9.889) Pub Date : 2020-07-17
    Amna Asif-Laidin,Christine Conesa,Amandine Bonnet,Camille Grison,Indranil Adhya,Rachid Menouni,Hélène Fayol,Noé Palmic,Joël Acker,Pascale Lesage

    Integration of transposable elements into the genome is mutagenic. Mechanisms targeting integrations into relatively safe locations, hence minimizing deleterious consequences for cell fitness, have emerged during evolution. In budding yeast, integration of the Ty1 LTR retrotransposon upstream of RNA polymerase III (Pol III)‐transcribed genes requires interaction between Ty1 integrase (IN1) and AC40

    更新日期:2020-09-01
  • The Alzheimer's disease-associated C99 fragment of APP regulates cellular cholesterol trafficking.
    EMBO J. (IF 9.889) Pub Date : 2020-08-31
    Jorge Montesinos,Marta Pera,Delfina Larrea,Cristina Guardia-Laguarta,Rishi R Agrawal,Kevin R Velasco,Taekyung D Yun,Irina G Stavrovskaya,Yimeng Xu,So Yeon Koo,Amanda M Snead,Andrew A Sproul,Estela Area-Gomez

    The link between cholesterol homeostasis and cleavage of the amyloid precursor protein (APP), and how this relationship relates to Alzheimer's disease (AD) pathogenesis, is still unknown. Cellular cholesterol levels are regulated through crosstalk between the plasma membrane (PM), where most cellular cholesterol resides, and the endoplasmic reticulum (ER), where the protein machinery that regulates

    更新日期:2020-08-31
  • A FAK conundrum is solved: activation and organization of focal adhesion kinase at the plasma membrane.
    EMBO J. (IF 9.889) Pub Date : 2020-08-31
    Florian Brod,Reinhard Fässler

    Focal adhesion kinase (FAK) is a central mediator of cell adhesion, acting both as a scaffold and as catalytically active kinase. Acebrón et al (2020) use cryo‐electron microscopy (cryo‐EM) to visualize the dramatic structural changes that occur upon FAK recruitment to the plasma membrane, which releases FAK autoinhibition and induces its oligomerization. Since activity control via autoinhibition and

    更新日期:2020-08-31
  • Roles of plant retinoblastoma protein: cell cycle and beyond.
    EMBO J. (IF 9.889) Pub Date : 2020-08-31
    Bénédicte Desvoyes,Crisanto Gutierrez

    The human retinoblastoma (RB1) protein is a tumor suppressor that negatively regulates cell cycle progression through its interaction with members of the E2F/DP family of transcription factors. However, RB‐related (RBR) proteins are an early acquisition during eukaryote evolution present in plant lineages, including unicellular algae, ancient plants (ferns, lycophytes, liverworts, mosses), gymnosperms

    更新日期:2020-08-31
  • LRRK2 and Rab10 coordinate macropinocytosis to mediate immunological responses in phagocytes.
    EMBO J. (IF 9.889) Pub Date : 2020-08-27
    Zhiyong Liu,Enquan Xu,Hien Tran Zhao,Tracy Cole,Andrew B West

    Genetic variation in LRRK2 associates with the susceptibility to Parkinson's disease, Crohn's disease, and mycobacteria infection. High expression of LRRK2 and its substrate Rab10 occurs in phagocytic cells in the immune system. In mouse and human primary macrophages, dendritic cells, and microglia‐like cells, we find that Rab10 specifically regulates a specialized form of endocytosis known as macropinocytosis

    更新日期:2020-08-28
  • Disrupting HIV-1 capsid formation causes cGAS sensing of viral DNA.
    EMBO J. (IF 9.889) Pub Date : 2020-08-27
    Rebecca P Sumner,Lauren Harrison,Emma Touizer,Thomas P Peacock,Matthew Spencer,Lorena Zuliani-Alvarez,Greg J Towers

    Detection of viral DNA by cyclic GMP‐AMP synthase (cGAS) is a first line of defence leading to the production of type I interferon (IFN). As HIV‐1 replication is not a strong inducer of IFN, we hypothesised that an intact capsid physically cloaks viral DNA from cGAS. To test this, we generated defective viral particles by treatment with HIV‐1 protease inhibitors or by genetic manipulation of gag. These

    更新日期:2020-08-27
  • CARD8 inflammasome activation triggers pyroptosis in human T cells.
    EMBO J. (IF 9.889) Pub Date : 2020-08-25
    Andreas Linder,Stefan Bauernfried,Yiming Cheng,Manuel Albanese,Christophe Jung,Oliver T Keppler,Veit Hornung

    Inflammasomes execute a unique type of cell death known as pyroptosis. Mostly characterized in myeloid cells, caspase‐1 activation downstream of an inflammasome sensor results in the cleavage and activation of gasdermin D (GSDMD), which then forms a lytic pore in the plasma membrane. Recently, CARD8 was identified as a novel inflammasome sensor that triggers pyroptosis in myeloid leukemia cells upon

    更新日期:2020-08-25
  • AP-3 vesicle uncoating occurs after HOPS-dependent vacuole tethering.
    EMBO J. (IF 9.889) Pub Date : 2020-08-25
    Jannis Schoppe,Muriel Mari,Erdal Yavavli,Kathrin Auffarth,Margarita Cabrera,Stefan Walter,Florian Fröhlich,Christian Ungermann

    Heterotetrameric adapter (AP) complexes cooperate with the small GTPase Arf1 or lipids in cargo selection, vesicle formation, and budding at endomembranes in eukaryotic cells. While most AP complexes also require clathrin as the outer vesicle shell, formation of AP‐3‐coated vesicles involved in Golgi‐to‐vacuole transport in yeast has been postulated to depend on Vps41, a subunit of the vacuolar HOPS

    更新日期:2020-08-25
  • γ-Secretase cleavage of the Alzheimer risk factor TREM2 is determined by its intrinsic structural dynamics.
    EMBO J. (IF 9.889) Pub Date : 2020-08-24
    Andrea Steiner,Kai Schlepckow,Bettina Brunner,Harald Steiner,Christian Haass,Franz Hagn

    Sequence variants of the microglial expressed TREM2 (triggering receptor expressed on myeloid cells 2) are a major risk factor for late onset Alzheimer's disease. TREM2 requires a stable interaction with DAP12 in the membrane to initiate signaling, which is terminated by TREM2 ectodomain shedding and subsequent intramembrane cleavage by γ‐secretase. To understand the structural basis for the specificity

    更新日期:2020-08-24
  • The RNA exosome complex degrades expanded hexanucleotide repeat RNA in C9orf72 FTLD/ALS.
    EMBO J. (IF 9.889) Pub Date : 2020-08-24
    Yuya Kawabe,Kohji Mori,Tomoko Yamashita,Shiho Gotoh,Manabu Ikeda

    Nucleotide repeat expansions in the C9orf72 gene cause frontotemporal lobar degeneration (FTLD) and amyotrophic lateral sclerosis (ALS). Transcribed repeat RNA accumulates within RNA foci and is also translated into toxic dipeptide repeat proteins (DPR). The mechanism of repeat RNA accumulation, however, remains unclear. The RNA exosome complex is a multimeric ribonuclease involved in degradation of

    更新日期:2020-08-24