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  • Streptococcus pneumoniae hijacks host autophagy by deploying CbpC as a decoy for Atg14 depletion
    EMBO Rep. (IF 8.383) Pub Date : 2020-04-02
    Sayaka Shizukuishi; Michinaga Ogawa; Satoko Matsunaga; Mikado Tomokiyo; Tadayoshi Ikebe; Shinya Fushinobu; Akihide Ryo; Makoto Ohnishi

    Pneumococcal cell surface‐exposed choline‐binding proteins (CBPs) play pivotal roles in multiple infectious processes with pneumococci. Intracellular pneumococci can be recognized at multiple steps during bactericidal autophagy. However, whether CBPs are involved in pneumococci‐induced autophagic processes remains unknown. In this study, we demonstrate that CbpC from S. pneumoniae strain TIGR4 activates

  • Regulation of epidermal differentiation through KDF1‐mediated deubiquitination of IKKα
    EMBO Rep. (IF 8.383) Pub Date : 2020-04-01
    Yuanyuan Li; Liangfeng Tang; Jiping Yue; Xuewen Gou; Anning Lin; Scott D Weatherbee; Xiaoyang Wu

    Progenitor cells at the basal layer of skin epidermis play an essential role in maintaining tissue homeostasis and enhancing wound repair in skin. The proliferation, differentiation, and cell death of epidermal progenitor cells have to be delicately regulated, as deregulation of this process can lead to many skin diseases, including skin cancers. However, the underlying molecular mechanisms involved

  • Gi‐coupled receptor activation potentiates Piezo2 currents via Gβγ
    EMBO Rep. (IF 8.383) Pub Date : 2020-03-29
    John Smith Del Rosario; Yevgen Yudin; Songxue Su; Cassandra M Hartle; Tooraj Mirshahi; Tibor Rohacs

    Mechanically activated Piezo2 channels are key players in somatosensory touch, but their regulation by cellular signaling pathways is poorly understood. Dorsal root ganglion (DRG) neurons express a variety of G‐protein‐coupled receptors that modulate the function of sensory ion channels. Gi‐coupled receptors are generally considered inhibitory, as they usually decrease excitability. Paradoxically,

  • SGTA associates with nascent membrane protein precursors
    EMBO Rep. (IF 8.383) Pub Date : 2020-03-25
    Pawel Leznicki; Stephen High

    The endoplasmic reticulum (ER) is a major site for membrane protein synthesis in eukaryotes. The majority of integral membrane proteins are delivered to the ER membrane via the co‐translational, signal recognition particle (SRP)‐dependent route. However, tail‐anchored proteins employ an alternative, post‐translational route(s) that relies on distinct factors such as a cytosolic protein quality control

  • Suppression of Ca2+ signals by EGR4 controls Th1 differentiation and anti‐cancer immunity in vivo
    EMBO Rep. (IF 8.383) Pub Date : 2020-03-25
    Jayati Mookerjee‐Basu; Robert Hooper; Scott Gross; Bryant Schultz; Christina K Go; Elsie Samakai; Jonathan Ladner; Emmanuelle Nicolas; Yuanyuan Tian; Bo Zhou; M Raza Zaidi; Warren Tourtellotte; Shan He; Yi Zhang; Dietmar J Kappes; Jonathan Soboloff

    While the zinc finger transcription factors EGR1, EGR2, and EGR3 are recognized as critical for T‐cell function, the role of EGR4 remains unstudied. Here, we show that EGR4 is rapidly upregulated upon TCR engagement, serving as a critical “brake” on T‐cell activation. Hence, TCR engagement of EGR4−/− T cells leads to enhanced Ca2+ responses, driving sustained NFAT activation and hyperproliferation

  • ECE2 regulates neurogenesis and neuronal migration during human cortical development
    EMBO Rep. (IF 8.383) Pub Date : 2020-03-24
    Isabel Y Buchsbaum; Pavel Kielkowski; Grazia Giorgio; Adam C O'Neill; Rossella Di Giaimo; Christina Kyrousi; Shahryar Khattak; Stephan A Sieber; Stephen P Robertson; Silvia Cappello

    During embryonic development, excitatory projection neurons migrate in the cerebral cortex giving rise to organised layers. Periventricular heterotopia (PH) is a group of aetiologically heterogeneous disorders in which a subpopulation of newborn projection neurons fails to initiate their radial migration to the cortex, ultimately resulting in bands or nodules of grey matter lining the lateral ventricles

  • PP2A phosphatase is required for dendrite pruning via actin regulation in Drosophila
    EMBO Rep. (IF 8.383) Pub Date : 2020-03-24
    Neele Wolterhoff; Ulrike Gigengack; Sebastian Rumpf

    Large‐scale pruning, the developmentally regulated degeneration of axons or dendrites, is an important specificity mechanism during neuronal circuit formation. The peripheral sensory class IV dendritic arborization (c4da) neurons of Drosophila larvae specifically prune their dendrites at the onset of metamorphosis in an ecdysone‐dependent manner. Dendrite pruning requires local cytoskeleton remodeling

  • Role of respiratory NADH oxidation in the regulation of Staphylococcus aureus virulence
    EMBO Rep. (IF 8.383) Pub Date : 2020-03-23
    Lici A Schurig‐Briccio; Paola K Parraga Solorzano; Andrea M Lencina; Jana N Radin; Grischa Y Chen; John‐Demian Sauer; Thomas E Kehl‐Fie; Robert B Gennis

    The success of Staphylococcus aureus as a pathogen is due to its capability of fine‐tuning its cellular physiology to meet the challenges presented by diverse environments, which allows it to colonize multiple niches within a single vertebrate host. Elucidating the roles of energy‐yielding metabolic pathways could uncover attractive therapeutic strategies and targets. In this work, we seek to determine

  • Mitochondrial DNA in inflammation and immunity
    EMBO Rep. (IF 8.383) Pub Date : 2020-03-23
    Joel S Riley; Stephen WG Tait

    Mitochondria are cellular organelles that orchestrate a vast range of biological processes, from energy production and metabolism to cell death and inflammation. Despite this seemingly symbiotic relationship, mitochondria harbour within them a potent agonist of innate immunity: their own genome. Release of mitochondrial DNA into the cytoplasm and out into the extracellular milieu activates a plethora

  • Protein phosphatase PP2A regulates microtubule orientation and dendrite pruning in Drosophila
    EMBO Rep. (IF 8.383) Pub Date : 2020-03-18
    Menglong Rui; Kay Siong Ng; Quan Tang; Shufeng Bu; Fengwei Yu

    Pruning that selectively eliminates inappropriate projections is crucial for sculpting neural circuits during development. During Drosophila metamorphosis, ddaC sensory neurons undergo dendrite‐specific pruning in response to the steroid hormone ecdysone. However, the understanding of the molecular mechanisms underlying dendrite pruning remains incomplete. Here, we show that protein phosphatase 2A

  • tRIP‐seq reveals repression of premature polyadenylation by co‐transcriptional FUS‐U1 snRNP assembly
    EMBO Rep. (IF 8.383) Pub Date : 2020-03-18
    Akio Masuda; Toshihiko Kawachi; Jun‐ichi Takeda; Bisei Ohkawara; Mikako Ito; Kinji Ohno

    RNA processing occurs co‐transcriptionally through the dynamic recruitment of RNA processing factors to RNA polymerase II (RNAPII). However, transcriptome‐wide identification of protein–RNA interactions specifically assembled on transcribing RNAPII is challenging. Here, we develop the targeted RNA immunoprecipitation sequencing (tRIP‐seq) method that detects protein–RNA interaction sites in thousands

  • Controlling Smad4 signaling with a Wip
    EMBO Rep. (IF 8.383) Pub Date : 2020-03-18
    Peter ten Dijke; David Baker

    Members of the transforming growth factor‐β (TGF‐β) family play key roles in embryogenesis and in maintaining tissue homeostasis, and their perturbation can result in a broad range of diseases. One way TGF‐β family signaling pathways are kept in check is by reversible (de)phosphorylation of intracellular Smad effectors. In this issue of EMBO Reports, Park et al [1] identify the phosphatase wild‐type

  • High‐grade mesenchymal pancreatic ductal adenocarcinoma drives stromal deactivation through CSF‐1
    EMBO Rep. (IF 8.383) Pub Date : 2020-03-16
    Anne Steins; Madelaine G van Mackelenbergh; Amber P van der Zalm; Remy Klaassen; Bryan Serrels; Sandrine G Goris; Hemant M Kocher; Cynthia Waasdorp; Joan H de Jong; Cansu Tekin; Marc G Besselink; Olivier R Busch; Marc J van de Vijver; Joanne Verheij; Frederike Dijk; Geertjan van Tienhoven; Johanna W Wilmink; Jan Paul Medema; Hanneke WM van Laarhoven; Maarten F Bijlsma

    Pancreatic ductal adenocarcinoma (PDAC) is characterized by an abundance of stroma. Multiple molecular classification efforts have identified a mesenchymal tumor subtype that is consistently characterized by high‐grade growth and poor clinical outcome. The relation between PDAC stroma and tumor subtypes is still unclear. Here, we aimed to identify how PDAC cells instruct the main cellular component

  • TLR4‐dependent shaping of the wound site by MSCs accelerates wound healing
    EMBO Rep. (IF 8.383) Pub Date : 2020-03-12
    Saira Munir; Abhijit Basu; Pallab Maity; Linda Krug; Philipp Haas; Dongsheng Jiang; Gudrun Strauss; Meinhard Wlaschek; Hartmut Geiger; Karmveer Singh; Karin Scharffetter‐Kochanek

    We here address the question whether the unique capacity of mesenchymal stem cells to re‐establish tissue homeostasis depends on their potential to sense pathogen‐associated molecular pattern and, in consequence, mount an adaptive response in the interest of tissue repair. After injection of MSCs primed with the bacterial wall component LPS into murine wounds, an unexpected acceleration of healing

  • TMEM135 regulates primary ciliogenesis through modulation of intracellular cholesterol distribution
    EMBO Rep. (IF 8.383) Pub Date : 2020-03-11
    Yunash Maharjan; Joon No Lee; Seong Ae Kwak; Raghbendra Kumar Dutta; Channy Park; Seong‐Kyu Choe; Raekil Park

    Recent evidence has linked the lysosomal cholesterol accumulation in Niemann–Pick type C1 with anomalies associated with primary ciliogenesis. Here, we report that perturbed intracellular cholesterol distribution imposed by lysosomal cholesterol accumulation during TMEM135 depletion is closely associated with impaired ciliogenesis. TMEM135 depletion does not affect the formation of the basal body and

  • Homeobox A4 suppresses vascular remodeling by repressing YAP/TEAD transcriptional activity
    EMBO Rep. (IF 8.383) Pub Date : 2020-03-09
    Masahiro Kimura; Takahiro Horie; Osamu Baba; Yuya Ide; Shuhei Tsuji; Randolph Ruiz Rodriguez; Toshimitsu Watanabe; Tomohiro Yamasaki; Chiharu Otani; Sijia Xu; Yui Miyasaka; Yasuhiro Nakashima; Takeshi Kimura; Koh Ono

    The Hippo signaling pathway is involved in the pathophysiology of various cardiovascular diseases. Yes‐associated protein (YAP) and transcriptional enhancer activator domain (TEAD) transcriptional factors, the main transcriptional complex of the Hippo pathway, were recently identified as modulators of phenotypic switching of vascular smooth muscle cells (VSMCs). However, the intrinsic regulator of

  • LncRNA GUARDIN suppresses cellular senescence through a LRP130‐PGC1α‐FOXO4‐p21‐dependent signaling axis
    EMBO Rep. (IF 8.383) Pub Date : 2020-03-09
    Xuedan Sun; Rick Francis Thorne; Xu Dong Zhang; Miao He; Jinming Li; Shanshan Feng; Xiaoying Liu; Mian Wu

    The long noncoding RNA GUARDIN functions to protect genome stability. Inhibiting GUARDIN expression can alter cell fate decisions toward senescence or apoptosis, but the underlying molecular signals are unknown. Here, we show that GUARDIN is an essential component of a transcriptional repressor complex involving LRP130 and PGC1α. GUARDIN acts as a scaffold to stabilize LRP130/PGC1α heterodimers and

  • Structure of RyR1 in native membranes
    EMBO Rep. (IF 8.383) Pub Date : 2020-03-09
    Wenbo Chen; Mikhail Kudryashev

    Ryanodine receptor 1 (RyR1) mediates excitation–contraction coupling by releasing Ca2+ from sarcoplasmic reticulum (SR) to the cytoplasm of skeletal muscle cells. RyR1 activation is regulated by several proteins from both the cytoplasm and lumen of the SR. Here, we report the structure of RyR1 from native SR membranes in closed and open states. Compared to the previously reported structures of purified

  • Exosomes take (germinal) center stage
    EMBO Rep. (IF 8.383) Pub Date : 2020-03-09
    Jennifer Pérez‐Boza; Dirk M Pegtel

    Efficient antibody production is a crucial step during immune responses leading to pathogen clearance and neutralization. Immune synapses, contact points between T and B lymphocytes in the presence of an antigen, are necessary to initiate the proliferation and differentiation of B cells in the germinal center. In this issue of EMBO Reports, Fernández‐Messina et al [1] present evidence of microRNA transfer

  • SIRT2‐dependent IDH1 deacetylation inhibits colorectal cancer and liver metastases
    EMBO Rep. (IF 8.383) Pub Date : 2020-03-05
    Bo Wang; Yingjiang Ye; Xin Yang; Boya Liu; Zhe Wang; Shuaiyi Chen; Kewei Jiang; Wei Zhang; Hongpeng Jiang; Harri Mustonen; Pauli Puolakkainen; Shan Wang; Jianyuan Luo; Zhanlong Shen

    Protein lysine acetylation affects colorectal cancer (CRC) distant metastasis through multiple pathways. In a previous proteomics screen, we found that isocitrate dehydrogenase 1 (IDH1) is hyperacetylated in CRC primary tumors and liver metastases. Here, we further investigate the function of IDH1 hyperacetylation at lysine 224 in CRC progression. We find that IDH1 K224 deacetylation promotes its enzymatic

  • Hippocampal CD39/ENTPD1 promotes mouse depression‐like behavior through hydrolyzing extracellular ATP
    EMBO Rep. (IF 8.383) Pub Date : 2020-03-05
    Qian‐Qian Cui; Zhuang‐Li Hu; Yuan‐Lang Hu; Xi Chen; Ji Wang; Li Mao; Xiao‐Jia Lu; Ming Ni; Jian‐Guo Chen; Fang Wang

    Emerging evidence implicates that low levels of ATP in the extracellular space may contribute to the pathophysiology of major depressive disorder (MDD). The concentration of extracellular ATP is regulated by its hydrolase ectonucleotide tri(di)phosphohydrolase (ENTPD). However, the role of ENTPD in depression remains poorly understood. Here we examine the role of CD39 (known as ENTPD1) in mouse depression‐like

  • USP1 deubiquitinates Akt to inhibit PI3K‐Akt‐FoxO signaling in muscle during prolonged starvation
    EMBO Rep. (IF 8.383) Pub Date : 2020-03-05
    Dana Goldbraikh; Danielle Neufeld; Yara Eid‐Mutlak; Inbal Lasry; Jennifer E Gilda; Anna Parnis; Shenhav Cohen

    PI3K‐Akt‐FoxO‐mTOR signaling is the central pathway controlling growth and metabolism in all cells. Ubiquitination of the protein kinase Akt prior to its phosphorylation is required for PI3K‐Akt activity. Here, we found that the deubiquitinating (DUB) enzyme USP1 removes K63‐linked polyubiquitin chains on Akt to restrict PI3K‐Akt‐FoxO signaling in mouse muscle during prolonged starvation. DUB screening

  • Small‐molecule inhibition of aging‐associated chromosomal instability delays cellular senescence
    EMBO Rep. (IF 8.383) Pub Date : 2020-03-05
    Monika Barroso‐Vilares; Joana C Macedo; Marta Reis; Jessica D Warren; Duane Compton; Elsa Logarinho

    Chromosomal instability (CIN) refers to the rate at which cells are unable to properly segregate whole chromosomes, leading to aneuploidy. Besides its prevalence in cancer cells and postulated implications in promoting tumorigenesis, studies in aneuploidy‐prone mouse models uncovered an unanticipated link between CIN and aging. Using young to old‐aged human dermal fibroblasts, we observed a dysfunction

  • Depression: a new enzyme AT play
    EMBO Rep. (IF 8.383) Pub Date : 2020-03-05
    Helena Caria Martins; Gerhard Schratt

    Neuronal activity is the main contributor to the high‐energy demand of the human brain. ATP is needed for the maintenance of ionic gradients, neurotransmitter transport, and release, as well as the signaling pathways that follow activation of post‐synaptic receptors. The inability to maintain a high supply of ATP through tight regulatory mechanisms can, therefore, have severe consequences for brain

  • lncRNA-DNA hybrids regulate distant genes.
    EMBO Rep. (IF 8.383) Pub Date : 2020-02-20
    Aina Maria Mas,Maite Huarte

    lncRNAs actively regulate gene expression. They contribute to chromosomal interactions at close or distant genomic regions, which, in turn, regulate transcription [1]. Ariel et al [2] reveal in a recent study a new molecular mechanism of the Arabidopsis lncRNA APOLO. The authors extend previously reported functions of APOLO in cis-regulation of chromosomal looping and transcription of its neighbor

  • Institutional ELN/LIMS deployment: Highly customizable ELN/LIMS platform as a cornerstone of digital transformation for life sciences research institutes.
    EMBO Rep. (IF 8.383) Pub Date : 2020-02-27
    Nicolas Argento

    The systematic recording and management of experimental data in academic life science research remains an open problem. EPFL engaged in a program of ELN/LIMS deployment 6 years ago, encountering a host of fundamental questions at the institutional level and in each single laboratory. Here, based on our experience we aim to share with research institute managers, PIs, and any scientists involved in

  • Mitochondrial DNA heteroplasmy in disease and targeted nuclease-based therapeutic approaches.
    EMBO Rep. (IF 8.383) Pub Date : 2020-02-19
    Nadee Nissanka,Carlos T Moraes

    Mitochondrial DNA (mtDNA) encodes a subset of the genes which are responsible for oxidative phosphorylation. Pathogenic mutations in the human mtDNA are often heteroplasmic, where wild-type mtDNA species co-exist with the pathogenic mtDNA and a bioenergetic defect is only seen when the pathogenic mtDNA percentage surpasses a threshold for biochemical manifestations. mtDNA segregation during germline

  • NAD(P) transhydrogenase has vital non-mitochondrial functions in malaria parasite transmission.
    EMBO Rep. (IF 8.383) Pub Date : 2020-01-17
    Sadia Saeed,Annie Z Tremp,Vikram Sharma,Edwin Lasonder,Johannes T Dessens

    Nicotinamide adenine dinucleotide (NAD) and its phosphorylated form (NADP) are vital for cell function in all organisms and form cofactors to a host of enzymes in catabolic and anabolic processes. NAD(P) transhydrogenases (NTHs) catalyse hydride ion transfer between NAD(H) and NADP(H). Membrane-bound NTH isoforms reside in the cytoplasmic membrane of bacteria, and the inner membrane of mitochondria

  • Golgi-associated microtubules are fast cargo tracks and required for persistent cell migration.
    EMBO Rep. (IF 8.383) Pub Date : 2020-01-27
    Huiwen Hao,Jiahao Niu,Boxin Xue,Qian Peter Su,Menghan Liu,Junsheng Yang,Jinshan Qin,Shujuan Zhao,Congying Wu,Yujie Sun

    Microtubules derived from the Golgi (Golgi MTs) have been implicated to play critical roles in persistent cell migration, but the underlying mechanisms remain elusive, partially due to the lack of direct observation of Golgi MT-dependent vesicular trafficking. Here, using super-resolution stochastic optical reconstruction microscopy (STORM), we discovered that post-Golgi cargos are more enriched on

  • A conserved ATG2-GABARAP family interaction is critical for phagophore formation.
    EMBO Rep. (IF 8.383) Pub Date : 2020-02-03
    Mihaela Bozic,Luuk van den Bekerom,Beth A Milne,Nicola Goodman,Lisa Roberston,Alan R Prescott,Thomas J Macartney,Nina Dawe,David G McEwan

    The intracellular trafficking pathway, macroautophagy, is a recycling and disposal service that can be upregulated during periods of stress to maintain cellular homeostasis. An essential phase is the elongation and closure of the phagophore to seal and isolate unwanted cargo prior to lysosomal degradation. Human ATG2A and ATG2B proteins, through their interaction with WIPI proteins, are thought to

  • RNF152 positively regulates TLR/IL-1R signaling by enhancing MyD88 oligomerization.
    EMBO Rep. (IF 8.383) Pub Date : 2020-01-13
    Mei-Guang Xiong,Zhi-Sheng Xu,Yu-Hui Li,Su-Yun Wang,Yan-Yi Wang,Yong Ran

    Toll-like receptors (TLRs) are important pattern recognition receptors (PRRs) that are critical for the defense against invading pathogens. IL-1β is an important pro-inflammatory cytokine that also plays pivotal roles in shaping the adaptive immune response. TLRs and interleukin-1 receptor (IL-1R) share similar cytosolic domains and signaling processes. In this study, we identify the E3 ubiquitin ligase

  • Npl3 stabilizes R-loops at telomeres to prevent accelerated replicative senescence.
    EMBO Rep. (IF 8.383) Pub Date : 2020-02-06
    Lara Pérez-Martínez,Merve Öztürk,Falk Butter,Brian Luke

    Telomere shortening rates must be regulated to prevent premature replicative senescence. TERRA R-loops become stabilized at critically short telomeres to promote their elongation through homology-directed repair (HDR), thereby counteracting senescence onset. Using a non-bias proteomic approach to detect telomere binding factors, we identified Npl3, an RNA-binding protein previously implicated in multiple

  • NBR1-mediated p62-liquid droplets enhance the Keap1-Nrf2 system.
    EMBO Rep. (IF 8.383) Pub Date : 2020-01-09
    Pablo Sánchez-Martín,Yu-Shin Sou,Shun Kageyama,Masato Koike,Satoshi Waguri,Masaaki Komatsu

    p62/SQSTM1 is a multivalent protein that has the ability to cause liquid-liquid phase separation and serves as a receptor protein that participates in cargo isolation during selective autophagy. This protein is also involved in the non-canonical activation of the Keap1-Nrf2 system, a major oxidative stress response pathway. Here, we show a role of neighbor of BRCA1 gene 1 (NBR1), an autophagy receptor

  • Cristae undergo continuous cycles of membrane remodelling in a MICOS-dependent manner.
    EMBO Rep. (IF 8.383) Pub Date : 2020-02-18
    Arun Kumar Kondadi,Ruchika Anand,Sebastian Hänsch,Jennifer Urbach,Thomas Zobel,Dane M Wolf,Mayuko Segawa,Marc Liesa,Orian S Shirihai,Stefanie Weidtkamp-Peters,Andreas S Reichert

    The mitochondrial inner membrane can reshape under different physiological conditions. How, at which frequency this occurs in living cells, and the molecular players involved are unknown. Here, we show using state-of-the-art live-cell stimulated emission depletion (STED) super-resolution nanoscopy that neighbouring crista junctions (CJs) dynamically appose and separate from each other in a reversible

  • Long non-coding RNA uc.291 controls epithelial differentiation by interfering with the ACTL6A/BAF complex.
    EMBO Rep. (IF 8.383) Pub Date : 2020-02-04
    Emanuele Panatta,Anna Maria Lena,Mara Mancini,Artem Smirnov,Alberto Marini,Riccardo Delli Ponti,Teresa Botta-Orfila,Gian Gaetano Tartaglia,Alessandro Mauriello,Xinna Zhang,George A Calin,Gerry Melino,Eleonora Candi

    The mechanisms that regulate the switch between epidermal progenitor state and differentiation are not fully understood. Recent findings indicate that the chromatin remodelling BAF complex (Brg1-associated factor complex or SWI/SNF complex) and the transcription factor p63 mutually recruit one another to open chromatin during epidermal differentiation. Here, we identify a long non-coding transcript

  • Tau acetylates and stabilizes β-catenin thereby promoting cell survival.
    EMBO Rep. (IF 8.383) Pub Date : 2020-01-13
    Enjie Liu,Qiuzhi Zhou,Ao-Ji Xie,Xiaoguang Li,Mengzhu Li,Jinwang Ye,Shihong Li,Dan Ke,Qun Wang,Zhi-Peng Xu,Li Li,Ying Yang,Gong-Ping Liu,Xiao-Chuan Wang,Hong-Lian Li,Jian-Zhi Wang

    Overexpressing Tau counteracts apoptosis and increases dephosphorylated β-catenin levels, but the underlying mechanisms are elusive. Here, we show that Tau can directly and robustly acetylate β-catenin at K49 in a concentration-, time-, and pH-dependent manner. β-catenin K49 acetylation inhibits its phosphorylation and its ubiquitination-associated proteolysis, thus increasing β-catenin protein levels

  • CRMP2 mediates Sema3F-dependent axon pruning and dendritic spine remodeling.
    EMBO Rep. (IF 8.383) Pub Date : 2020-01-09
    Jakub Ziak,Romana Weissova,Kateřina Jeřábková,Martina Janikova,Roy Maimon,Tomas Petrasek,Barbora Pukajova,Marie Kleisnerova,Mengzhe Wang,Monika S Brill,Petr Kasparek,Xunlei Zhou,Gonzalo Alvarez-Bolado,Radislav Sedlacek,Thomas Misgeld,Ales Stuchlik,Eran Perlson,Martin Balastik

    Regulation of axon guidance and pruning of inappropriate synapses by class 3 semaphorins are key to the development of neural circuits. Collapsin response mediator protein 2 (CRMP2) has been shown to regulate axon guidance by mediating semaphorin 3A (Sema3A) signaling; however, nothing is known about its role in synapse pruning. Here, using newly generated crmp2-/- mice we demonstrate that CRMP2 has

  • Interleukin-12/23 deficiency differentially affects pathology in male and female Alzheimer's disease-like mice.
    EMBO Rep. (IF 8.383) Pub Date : 2020-01-30
    Pascale Eede,Juliane Obst,Eileen Benke,Genevieve Yvon-Durocher,Bernhard C Richard,Niclas Gimber,Jan Schmoranzer,Annett Böddrich,Erich E Wanker,Stefan Prokop,Frank L Heppner

    Pathological aggregation of amyloid-β (Aβ) is a main hallmark of Alzheimer's disease (AD). Recent genetic association studies have linked innate immune system actions to AD development, and current evidence suggests profound gender differences in AD pathogenesis. Here, we characterise gender-specific pathologies in the APP23 AD-like mouse model and find that female mice show stronger amyloidosis and

  • The mechanoreceptor DEG-1 regulates cold tolerance in Caenorhabditis elegans.
    EMBO Rep. (IF 8.383) Pub Date : 2020-02-03
    Natsune Takagaki,Akane Ohta,Kohei Ohnishi,Akira Kawanabe,Yohei Minakuchi,Atsushi Toyoda,Yuichiro Fujiwara,Atsushi Kuhara

    Caenorhabditis elegans mechanoreceptors located in ASG sensory neurons have been found to sense ambient temperature, which is a key trait for animal survival. Here, we show that experimental loss of xanthine dehydrogenase (XDH-1) function in AIN and AVJ interneurons results in reduced cold tolerance and atypical neuronal response to changes in temperature. These interneurons connect with upstream neurons

  • ABCA12 regulates insulin secretion from β-cells.
    EMBO Rep. (IF 8.383) Pub Date : 2020-02-18
    Gloria M Ursino,Ying Fu,Denny L Cottle,Nigora Mukhamedova,Lynelle K Jones,Hann Low,Ming Shen Tham,Wan Jun Gan,Natalie A Mellett,Partha P Das,Jacquelyn M Weir,Michael Ditiatkovski,Stacey Fynch,Peter Thorn,Helen E Thomas,Peter J Meikle,Helena C Parkington,Ian M Smyth,Dmitri Sviridov

    Dysregulation of lipid homeostasis is intimately associated with defects in insulin secretion, a key feature of type 2 diabetes. Here, we explore the role of the putative lipid transporter ABCA12 in regulating insulin secretion from β-cells. Mice with β-cell-specific deletion of Abca12 display impaired glucose-stimulated insulin secretion and eventual islet inflammation and β-cell death. ABCA12's action

  • Muscle-derived GDF15 drives diurnal anorexia and systemic metabolic remodeling during mitochondrial stress.
    EMBO Rep. (IF 8.383) Pub Date : 2020-02-06
    Mario Ost,Carla Igual Gil,Verena Coleman,Susanne Keipert,Sotirios Efstathiou,Veronika Vidic,Miriam Weyers,Susanne Klaus

    Mitochondrial dysfunction promotes metabolic stress responses in a cell-autonomous as well as organismal manner. The wasting hormone growth differentiation factor 15 (GDF15) is recognized as a biomarker of mitochondrial disorders, but its pathophysiological function remains elusive. To test the hypothesis that GDF15 is fundamental to the metabolic stress response during mitochondrial dysfunction, we

  • IGF1R regulates retrograde axonal transport of signalling endosomes in motor neurons.
    EMBO Rep. (IF 8.383) Pub Date : 2020-02-07
    Alexander D Fellows,Elena R Rhymes,Katherine L Gibbs,Linda Greensmith,Giampietro Schiavo

    Signalling endosomes are essential for trafficking of activated ligand-receptor complexes and their distal signalling, ultimately leading to neuronal survival. Although deficits in signalling endosome transport have been linked to neurodegeneration, our understanding of the mechanisms controlling this process remains incomplete. Here, we describe a new modulator of signalling endosome trafficking,

  • A revised model of TRAIL-R2 DISC assembly explains how FLIP(L) can inhibit or promote apoptosis.
    EMBO Rep. (IF 8.383) Pub Date : 2020-02-03
    Luke M Humphreys,Jennifer P Fox,Catherine A Higgins,Joanna Majkut,Tamas Sessler,Kirsty McLaughlin,Christopher McCann,Jamie Z Roberts,Nyree T Crawford,Simon S McDade,Christopher J Scott,Timothy Harrison,Daniel B Longley

    The long FLIP splice form FLIP(L) can act as both an inhibitor and promoter of caspase-8 at death-inducing signalling complexes (DISCs) formed by death receptors such as TRAIL-R2 and related intracellular complexes such as the ripoptosome. Herein, we describe a revised DISC assembly model that explains how FLIP(L) can have these opposite effects by defining the stoichiometry (with respect to caspase-8)

  • WDR63 inhibits Arp2/3-dependent actin polymerization and mediates the function of p53 in suppressing metastasis.
    EMBO Rep. (IF 8.383) Pub Date : 2020-03-04
    Kailiang Zhao,Decai Wang,Xiaolong Zhao,Chenfeng Wang,Yongxiang Gao,Kaiyue Liu,Fang Wang,Xianning Wu,Xuejuan Wang,Linfeng Sun,Jianye Zang,Yide Mei

    Accumulating evidence suggests that p53 plays a suppressive role in cancer metastasis, yet the underlying mechanism remains largely unclear. Regulation of actin dynamics is essential for the control of cell migration, which is an important step in metastasis. The Arp2/3 complex is a major nucleation factor to initiate branched actin polymerization that drives cell migration. However, it is unknown

  • N-acetyl-l-tyrosine is an intrinsic triggering factor of mitohormesis in stressed animals.
    EMBO Rep. (IF 8.383) Pub Date : 2020-03-02
    Takashi Matsumura,Outa Uryu,Fumikazu Matsuhisa,Keiji Tajiri,Hitoshi Matsumoto,Yoichi Hayakawa

    Under stress conditions, mitochondria release low levels of reactive oxygen species (ROS), which triggers a cytoprotective response, called "mitohormesis". It still remains unclear how mitochondria respond to stress-derived stimuli and release a low level of ROS. Here, we show that N-acetyl-l-tyrosine (NAT) functions as a plausible intrinsic factor responsible for these tasks in stressed animals. NAT

  • Cripto shapes macrophage plasticity and restricts EndMT in injured and diseased skeletal muscle.
    EMBO Rep. (IF 8.383) Pub Date : 2020-02-27
    Francescopaolo Iavarone,Ombretta Guardiola,Alessandra Scagliola,Gennaro Andolfi,Federica Esposito,Antonio Serrano,Eusebio Perdiguero,Silvia Brunelli,Pura Muñoz-Cánoves,Gabriella Minchiotti

    Macrophages are characterized by a high plasticity in response to changes in tissue microenvironment, which allows them to acquire different phenotypes and to exert essential functions in complex processes, such as tissue regeneration. Here, we report that the membrane protein Cripto plays a key role in shaping macrophage plasticity in skeletal muscle during regeneration and disease. Conditional deletion

  • Wip1 regulates Smad4 phosphorylation and inhibits TGF-β signaling.
    EMBO Rep. (IF 8.383) Pub Date : 2020-02-27
    Dong-Seok Park,Gang-Ho Yoon,Eun-Young Kim,Taehyeong Lee,Kyuhee Kim,Peter Cw Lee,Eun-Ju Chang,Sun-Cheol Choi

    The tumor suppressor Smad4, a key mediator of the TGF-β/BMP pathways, is essential for development and tissue homeostasis. Phosphorylation of Smad4 in its linker region catalyzed by the mitogen-activated protein kinase (MAPK) plays a pivotal role in regulating its transcriptional activity and stability. In contrast, roles of Smad4 dephosphorylation as a control mechanism of TGF-β/BMP signaling and

  • Organismal benefits of transcription speed control at gene boundaries.
    EMBO Rep. (IF 8.383) Pub Date : 2020-02-27
    Xueyuan Leng,Maxim Ivanov,Peter Kindgren,Indranil Malik,Axel Thieffry,Peter Brodersen,Albin Sandelin,Craig D Kaplan,Sebastian Marquardt

    RNA polymerase II (RNAPII) transcription is crucial for gene expression. RNAPII density peaks at gene boundaries, associating these key regions for gene expression control with limited RNAPII movement. The connections between RNAPII transcription speed and gene regulation in multicellular organisms are poorly understood. Here, we directly modulate RNAPII transcription speed by point mutations in the

  • Plants, climate and humans: Plant intelligence changes everything.
    EMBO Rep. (IF 8.383) Pub Date : 2020-02-27
    František Baluška,Stefano Mancuso

    Plants play a more active role in shaping their environment than most climate models assume. Understanding their specific behavior could have profound impact on predicting future climate changes.

  • Human RAP1 specifically protects telomeres of senescent cells from DNA damage
    EMBO Rep. (IF 8.383) Pub Date : 2020-02-25
    Liudmyla Lototska; Jia‐Xing Yue; Jing Li; Marie‐Josèphe Giraud‐Panis; Zhou Songyang; Nicola J Royle; Gianni Liti; Jing Ye; Eric Gilson; Aaron Mendez‐Bermudez

    Repressor/activator protein 1 (RAP1) is a highly evolutionarily conserved protein found at telomeres. Although yeast Rap1 is a key telomere capping protein preventing non‐homologous end joining (NHEJ) and consequently telomere fusions, its role at mammalian telomeres in vivo is still controversial. Here, we demonstrate that RAP1 is required to protect telomeres in replicative senescent human cells

  • It is not just about money: Research funding for bold innovative projects is held back by a variety of factors, not just a lack of finances.
    EMBO Rep. (IF 8.383) Pub Date : 2020-02-25
    Philip Hunter

    Many scientists are concerned that academic research has become too conservative. It is not a lack of money but a confluence of factors that prevent support for innovative, long-term research projects.

  • Proteasome mapping reveals sexual dimorphism in tissue-specific sensitivity to protein aggregations.
    EMBO Rep. (IF 8.383) Pub Date : 2020-02-23
    Edmund Charles Jenkins,Nagma Shah,Maria Gomez,Gabriella Casalena,Dazhi Zhao,Timothy C Kenny,Sara Rose Guariglia,Giovanni Manfredi,Doris Germain

    Defects in the proteasome can result in pathological proteinopathies. However, the pathogenic role of sex- and tissue-specific sensitivity to proteotoxic stress remains elusive. Here, we map the proteasome activity across nine tissues, in male and female mice, and demonstrate strong sexual dimorphism in proteasome activity, where females have significantly higher activity in several tissues. Further

  • Chemokines and galectins form heterodimers to modulate inflammation.
    EMBO Rep. (IF 8.383) Pub Date : 2020-02-21
    Veit Eckardt,Michelle C Miller,Xavier Blanchet,Rundan Duan,Julian Leberzammer,Johan Duchene,Oliver Soehnlein,Remco Ta Megens,Anna-Kristin Ludwig,Aurelio Dregni,Alexander Faussner,Kanin Wichapong,Hans Ippel,Ingrid Dijkgraaf,Herbert Kaltner,Yvonne Döring,Kiril Bidzhekov,Tilman M Hackeng,Christian Weber,Hans-Joachim Gabius,Philipp von Hundelshausen,Kevin H Mayo

    Chemokines and galectins are simultaneously upregulated and mediate leukocyte recruitment during inflammation. Until now, these effector molecules have been considered to function independently. Here, we tested the hypothesis that they form molecular hybrids. By systematically screening chemokines for their ability to bind galectin-1 and galectin-3, we identified several interacting pairs, such as

  • MSCs rescue impaired wound healing in a murine LAD1 model by adaptive responses to low TGF-β1 levels.
    EMBO Rep. (IF 8.383) Pub Date : 2020-02-21
    Dongsheng Jiang,Karmveer Singh,Jana Muschhammer,Susanne Schatz,Anca Sindrilaru,Evgenia Makrantonaki,Yu Qi,Meinhard Wlaschek,Karin Scharffetter-Kochanek

    Mutations in the CD18 gene encoding the common β-chain of β2 integrins result in impaired wound healing in humans and mice suffering from leukocyte adhesion deficiency syndrome type 1 (LAD1). Transplantation of adipose tissue-derived mesenchymal stem cells (MSCs) restores normal healing of CD18-/- wounds by restoring the decreased TGF-β1 concentrations. TGF-β1 released from MSCs leads to enhanced myofibroblast

  • Linking m6 A to Wnt signaling.
    EMBO Rep. (IF 8.383) Pub Date : 2020-02-20
    Xiao-Min Liu,Shu-Bing Qian

    N6 -methyladenosine (m6 A) has emerged as a crucial molecular code to influence pluripotency and differentiation of diverse stem cells. A study in this issue now shows that, in intestinal stem cells, the m6 A reader protein YTHDF1 directs translational control of stemness in both m6 A- and Wnt-dependent manner [1].

  • The courage to change science.
    EMBO Rep. (IF 8.383) Pub Date : 2020-02-20
    Tiago Fleming Outeiro

    Bureaucracy, performance assessment and other pressures increasingly encroach on scientists' ability to do science. The research community as a whole needs to address these perils.

  • Transfer of extracellular vesicle-microRNA controls germinal center reaction and antibody production.
    EMBO Rep. (IF 8.383) Pub Date : 2020-02-19
    Lola Fernández-Messina,Ana Rodríguez-Galán,Virginia G de Yébenes,Cristina Gutiérrez-Vázquez,Sandra Tenreiro,Miguel C Seabra,Almudena R Ramiro,Francisco Sánchez-Madrid

    Intercellular communication orchestrates effective immune responses against disease-causing agents. Extracellular vesicles (EVs) are potent mediators of cell-cell communication. EVs carry bioactive molecules, including microRNAs, which modulate gene expression and function in the recipient cell. Here, we show that formation of cognate primary T-B lymphocyte immune contacts promotes transfer of a very

  • Loss of non-canonical KCC2 functions promotes developmental apoptosis of cortical projection neurons.
    EMBO Rep. (IF 8.383) Pub Date : 2020-02-17
    Martina Mavrovic,Pavel Uvarov,Eric Delpire,Laszlo Vutskits,Kai Kaila,Martin Puskarjov

    KCC2, encoded in humans by the SLC12A5 gene, is a multifunctional neuron-specific protein initially identified as the chloride (Cl- ) extruder critical for hyperpolarizing GABAA receptor currents. Independently of its canonical function as a K-Cl cotransporter, KCC2 regulates the actin cytoskeleton via molecular interactions mediated through its large intracellular C-terminal domain (CTD). Contrary

  • YTHDF1-mediated translation amplifies Wnt-driven intestinal stemness.
    EMBO Rep. (IF 8.383) Pub Date : 2020-02-17
    Bing Han,Sujun Yan,Saisai Wei,Jie Xiang,Kangli Liu,Zhanghui Chen,Rongpan Bai,Jinghao Sheng,Zhengping Xu,Xiangwei Gao

    N6-methyladenosine (m6 A) mRNA methylation has emerged as an important player in many biological processes by regulating gene expression. However, its roles in intestinal stem cell (ISC) homeostasis remain largely unknown. Here, we report that YTHDF1, an m6 A reader, is highly expressed in ISCs and its expression is upregulated by Wnt signaling at the translational level. Whereas YTHDF1 is dispensable

  • Dynamic expression of tRNA-derived small RNAs define cellular states.
    EMBO Rep. (IF 8.383) Pub Date : 2019-06-12
    Srikar Krishna,Daniel Gr Yim,Vairavan Lakshmanan,Varsha Tirumalai,Judice Ly Koh,Jung Eun Park,Jit Kong Cheong,Joo Leng Low,Michelle Js Lim,Siu Kwan Sze,Padubidri Shivaprasad,Akash Gulyani,Srikala Raghavan,Dasaradhi Palakodeti,Ramanuj DasGupta
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全球疫情及响应:BMC Medicine专题征稿