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  • COVID‐19 lessons from the dish: Dissecting CNS manifestations through brain organoids
    EMBO J. (IF 9.889) Pub Date : 2020-12-02
    Nicolò Caporale; Giuseppe Testa

    COVID‐19 is increasingly understood as a systemic disease with pathogenic manifestations beyond the respiratory tract. Recent work by Ramani et al (2020) dissects the cellular and molecular mechanisms of SARS‐CoV‐2’s neurotrophic properties, using viral exposure of human brain organoids. Their findings highlight neurons as primary target of cerebral SARS‐CoV‐2 infection and uncover its Tau‐related

    更新日期:2021-01-15
  • Stressin’ and slicin’: stress‐induced tRNA fragmentation codon‐adapts translation to repress cell growth
    EMBO J. (IF 9.889) Pub Date : 2020-12-21
    Nicola Guzzi; Cristian Bellodi

    Transfer RNAs (tRNAs) are central adaptors that decode genetic information during translation and have been long considered static cellular components. However, whether dynamic changes in tRNAs and tRNA‐derived fragments actively contribute to gene regulation remains debated. In this issue, Huh et al (2020) highlight tyrosine tRNAGUA fragmentation at the nexus of an evolutionarily conserved adaptive

    更新日期:2021-01-15
  • Membrane protein biogenesis by the EMC
    EMBO J. (IF 9.889) Pub Date : 2020-12-21
    Sara Alvira; Robin A Corey; Ian Collinson; Karin Römisch

    The endoplasmic reticulum (ER) membrane protein complex (EMC) was identified over a decade ago in a genetic screen for ER protein homeostasis. The EMC inserts transmembrane domains (TMDs) with limited hydrophobicity. Two recent cryo‐EM structures, and a third model based on partial high‐ and low‐resolution structures, suggest how this is accomplished.

    更新日期:2021-01-15
  • Rabl2 GTP hydrolysis licenses BBSome‐mediated export to fine‐tune ciliary signaling
    EMBO J. (IF 9.889) Pub Date : 2020-11-26
    Shichao Duan; Hao Li; Yirong Zhang; Suming Yang; Yawen Chen; Benhua Qiu; Cheng Huang; Juan Wang; Jinsong Li; Xueliang Zhu; Xiumin Yan

    Cilia of higher animals sense various environmental stimuli. Proper ciliary signaling requires appropriate extent of BBSome‐mediated export of membrane receptors across ciliary barrier transition zone (TZ) through retrograde intraflagellar transport (IFT) machinery. How the barrier passage is controlled, however, remains unknown. Here, we show that small GTPase Rabl2 functions as a molecular switch

    更新日期:2021-01-15
  • A stress‐induced tyrosine‐tRNA depletion response mediates codon‐based translational repression and growth suppression
    EMBO J. (IF 9.889) Pub Date : 2020-12-21
    Doowon Huh; Maria C Passarelli; Jenny Gao; Shahnoza N Dusmatova; Clara Goin; Lisa Fish; Alexandra M Pinzaru; Henrik Molina; Zhiji Ren; Elizabeth A McMillan; Hosseinali Asgharian; Hani Goodarzi; Sohail F Tavazoie

    Eukaryotic transfer RNAs can become selectively fragmented upon various stresses, generating tRNA‐derived small RNA fragments. Such fragmentation has been reported to impact a small fraction of the tRNA pool and thus presumed to not directly impact translation. We report that oxidative stress can rapidly generate tyrosine‐tRNAGUA fragments in human cells—causing significant depletion of the precursor

    更新日期:2021-01-15
  • Cell softness regulates tumorigenicity and stemness of cancer cells
    EMBO J. (IF 9.889) Pub Date : 2020-12-04
    Jiadi Lv; Yaoping Liu; Feiran Cheng; Jiping Li; Yabo Zhou; Tianzhen Zhang; Nannan Zhou; Cong Li; Zhenfeng Wang; Longfei Ma; Mengyu Liu; Qiang Zhu; Xiaohan Liu; Ke Tang; Jingwei Ma; Huafeng Zhang; Jing Xie; Yi Fang; Haizeng Zhang; Ning Wang; Yuying Liu; Bo Huang

    Identifying and sorting highly tumorigenic and metastatic tumor cells from a heterogeneous cell population is a daunting challenge. Here, we show that microfluidic devices can be used to sort marker‐based heterogeneous cancer stem cells (CSC) into mechanically stiff and soft subpopulations. The isolated soft tumor cells (< 400 Pa) but not the stiff ones (> 700 Pa) can form a tumor in immunocompetent

    更新日期:2021-01-15
  • The E3 ubiquitin ligase Peli1 regulates the metabolic actions of mTORC1 to suppress antitumor T cell responses
    EMBO J. (IF 9.889) Pub Date : 2020-11-20
    Chun‐Jung Ko; Lingyun Zhang; Zuliang Jie; Lele Zhu; Xiaofei Zhou; Xiaoping Xie; Tianxiao Gao; Jin‐Young Yang; Xuhong Cheng; Shao‐Cong Sun

    Metabolic fitness of T cells is crucial for immune responses against infections and tumorigenesis. Both the T cell receptor (TCR) signal and environmental cues contribute to the induction of T cell metabolic reprogramming, but the underlying mechanism is incompletely understood. Here, we identified the E3 ubiquitin ligase Peli1 as an important regulator of T cell metabolism and antitumor immunity.

    更新日期:2021-01-15
  • A new linear cyclin docking motif that mediates exclusively S‐phase CDK‐specific signaling
    EMBO J. (IF 9.889) Pub Date : 2020-11-19
    Ilona Faustova; Luka Bulatovic; Frida Matiyevskaya; Ervin Valk; Mihkel Örd; Mart Loog

    Cyclin‐dependent kinases (CDKs), the master regulators of cell division, are activated by different cyclins at different cell cycle stages. In addition to being activators of CDKs, cyclins recognize various linear motifs to target CDK activity to specific proteins. We uncovered a cyclin docking motif, NLxxxL, that contributes to phosphorylation‐dependent degradation of the CDK inhibitor Far1 at the

    更新日期:2021-01-15
  • Nucleolar c‐Myc recruitment by a Vibrio T3SS effector promotes host cell proliferation and bacterial virulence
    EMBO J. (IF 9.889) Pub Date : 2020-12-21
    Maozhi Hu; Yibei Zhang; Dan Gu; Xiang Chen; Matthew K Waldor; Xiaohui Zhou

    Pathogen type 3 secretion systems (T3SS) manipulate host cell pathways by directly delivering effector proteins into host cells. In Vibrio parahaemolyticus, the leading cause of bacterial seafood‐borne diarrheal disease, we showed that a T3SS effector, VgpA, localizes to the host cell nucleolus where it binds Epstein–Barr virus nuclear antigen 1‐binding protein 2 (EBP2). An amino acid substitution

    更新日期:2021-01-15
  • A microtubule‐LUZP1 association around tight junction promotes epithelial cell apical constriction
    EMBO J. (IF 9.889) Pub Date : 2020-12-21
    Tomoki Yano; Kazuto Tsukita; Hatsuho Kanoh; Shogo Nakayama; Hiroka Kashihara; Tomoaki Mizuno; Hiroo Tanaka; Takeshi Matsui; Yuhei Goto; Akira Komatsubara; Kazuhiro Aoki; Ryosuke Takahashi; Atsushi Tamura; Sachiko Tsukita

    Apical constriction is critical for epithelial morphogenesis, including neural tube formation. Vertebrate apical constriction is induced by di‐phosphorylated myosin light chain (ppMLC)‐driven contraction of actomyosin‐based circumferential rings (CRs), also known as perijunctional actomyosin rings, around apical junctional complexes (AJCs), mainly consisting of tight junctions (TJs) and adherens junctions

    更新日期:2021-01-15
  • GSK3α, not GSK3β, drives hippocampal NMDAR‐dependent LTD via tau‐mediated spine anchoring
    EMBO J. (IF 9.889) Pub Date : 2020-11-16
    Jonathan E Draffin; Carla Sánchez‐Castillo; Alba Fernández‐Rodrigo; Xavier Sánchez‐Sáez; Jesús Ávila; Florence F Wagner; José A Esteban

    Glycogen synthase kinase‐3 (GSK3) is an important signalling protein in the brain and modulates different forms of synaptic plasticity. Neuronal functions of GSK3 are typically attributed to one of its two isoforms, GSK3β, simply because of its prevalent expression in the brain. Consequently, the importance of isoform‐specific functions of GSK3 in synaptic plasticity has not been fully explored. We

    更新日期:2021-01-15
  • Inactive variants of death receptor p75NTR reduce Alzheimer’s neuropathology by interfering with APP internalization
    EMBO J. (IF 9.889) Pub Date : 2020-12-01
    Chenju Yi; Ket Yin Goh; Lik‐Wei Wong; Ajeena Ramanujan; Kazuhiro Tanaka; Sreedharan Sajikumar; Carlos F. Ibáñez

    A prevalent model of Alzheimer’s disease (AD) pathogenesis postulates the generation of neurotoxic fragments derived from the amyloid precursor protein (APP) after its internalization to endocytic compartments. The molecular pathways that regulate APP internalization and intracellular trafficking in neurons are incompletely understood. Here, we report that 5xFAD mice, an animal model of AD, expressing

    更新日期:2021-01-15
  • The calcium transporter ANNEXIN1 mediates cold‐induced calcium signaling and freezing tolerance in plants
    EMBO J. (IF 9.889) Pub Date : 2020-12-29
    Qiangbo Liu; Yanglin Ding; Yiting Shi; Liang Ma; Yi Wang; Chunpeng Song; Katie A Wilkins; Julia M Davies; Heather Knight; Marc R Knight; Zhizhong Gong; Yan Guo; Shuhua Yang

    The transient elevation of cytosolic free calcium concentration ([Ca2+]cyt) induced by cold stress is a well‐established phenomenon; however, the underlying mechanism remains elusive. Here, we report that the Ca2+‐permeable transporter ANNEXIN1 (AtANN1) mediates cold‐triggered Ca2+ influx and freezing tolerance in Arabidopsis thaliana. The loss of function of AtANN1 substantially impaired freezing

    更新日期:2021-01-15
  • Human CST complex protects stalled replication forks by directly blocking MRE11 degradation of nascent‐strand DNA
    EMBO J. (IF 9.889) Pub Date : 2020-11-19
    Xinxing Lyu; Kai‐Hang Lei; Pau Biak Sang; Olga Shiva; Megan Chastain; Peter Chi; Weihang Chai

    Degradation and collapse of stalled replication forks are main sources of genomic instability, yet the molecular mechanisms for protecting forks from degradation/collapse are not well understood. Here, we report that human CST (CTC1‐STN1‐TEN1) proteins, which form a single‐stranded DNA‐binding complex, localize at stalled forks and protect stalled forks from degradation by the MRE11 nuclease. CST deficiency

    更新日期:2021-01-15
  • ADP‐ribosylation of histone variant H2AX promotes base excision repair
    EMBO J. (IF 9.889) Pub Date : 2020-12-02
    Qian Chen; Chunjing Bian; Xin Wang; Xiuhua Liu; Muzaffer Ahmad Kassab; Yonghao Yu; Xiaochun Yu

    Optimal DNA damage response is associated with ADP‐ribosylation of histones. However, the underlying molecular mechanism of DNA damage‐induced histone ADP‐ribosylation remains elusive. Herein, using unbiased mass spectrometry, we identify that glutamate residue 141 (E141) of variant histone H2AX is ADP‐ribosylated following oxidative DNA damage. In‐depth studies performed with wild‐type H2AX and the

    更新日期:2021-01-15
  • Phosphoproteomics reveals novel modes of function and inter‐relationships among PIKKs in response to genotoxic stress
    EMBO J. (IF 9.889) Pub Date : 2020-11-20
    Sapir Schlam‐Babayov; Ariel Bensimon; Michal Harel; Tamar Geiger; Ruedi Aebersold; Yael Ziv; Yosef Shiloh

    The DNA damage response (DDR) is a complex signaling network that relies on cascades of protein phosphorylation, which are initiated by three protein kinases of the family of PI3‐kinase‐related protein kinases (PIKKs): ATM, ATR, and DNA‐PK. ATM is missing or inactivated in the genome instability syndrome, ataxia‐telangiectasia (A‐T). The relative shares of these PIKKs in the response to genotoxic stress

    更新日期:2021-01-15
  • Multiplexed CRISPR/CAS9‐mediated engineering of pre‐clinical mouse models bearing native human B cell receptors
    EMBO J. (IF 9.889) Pub Date : 2020-12-01
    Xuesong Wang; Rashmi Ray; Sven Kratochvil; Eleonora Melzi; Ying‐Cing Lin; Sophie Giguere; Liling Xu; John Warner; Diane Cheon; Alessia Liguori; Bettina Groschel; Nicole Phelps; Yumiko Adachi; Ryan Tingle; Lin Wu; Shane Crotty; Kathrin H Kirsch; Usha Nair; William R Schief; Facundo D Batista

    B‐cell receptor (BCR) knock‐in (KI) mouse models play an important role in vaccine development and fundamental immunological studies. However, the time required to generate them poses a bottleneck. Here we report a one‐step CRISPR/Cas9 KI methodology to combine the insertion of human germline immunoglobulin heavy and light chains at their endogenous loci in mice. We validate this technology with the

    更新日期:2021-01-15
  • ZSP‐1 is a Z granule surface protein required for Z granule fluidity and germline immortality in Caenorhabditis elegans
    EMBO J. (IF 9.889) Pub Date : 2021-01-13
    Gang Wan; Lakshya Bajaj; Brandon Fields; Anne E Dodson; Daniel Pagano; Yuhan Fei; Scott Kennedy

    Germ granules are biomolecular condensates that form in germ cells of all/most animals, where they regulate mRNA expression to promote germ cell function and totipotency. In the adult Caenorhabditis elegans germ cell, these granules are composed of at least four distinct sub‐compartments, one of which is the Z granule. To better understand the role of the Z granule in germ cell biology, we conducted

    更新日期:2021-01-13
  • Molecular mechanisms and physiological functions of mitophagy
    EMBO J. (IF 9.889) Pub Date : 2021-01-13
    Mashun Onishi; Koji Yamano; Miyuki Sato; Noriyuki Matsuda; Koji Okamoto

    Degradation of mitochondria via a selective form of autophagy, named mitophagy, is a fundamental mechanism conserved from yeast to humans that regulates mitochondrial quality and quantity control. Mitophagy is promoted via specific mitochondrial outer membrane receptors, or ubiquitin molecules conjugated to proteins on the mitochondrial surface leading to the formation of autophagosomes surrounding

    更新日期:2021-01-13
  • Cell death pathways: intricate connections and disease implications
    EMBO J. (IF 9.889) Pub Date : 2021-01-13
    Matthias Kist; Domagoj Vucic

    Various forms of cell death have been identified over the last decades with each relying on a different subset of proteins for the activation and execution of their respective pathway(s). In addition to the three best characterized pathways—apoptosis, necroptosis, and pyroptosis—other forms of regulated cell death including autophagy‐dependent cell death (ADCD), mitochondrial permeability transition

    更新日期:2021-01-13
  • An organoid‐derived bronchioalveolar model for SARS‐CoV‐2 infection of human alveolar type II‐like cells
    EMBO J. (IF 9.889) Pub Date : 2021-01-11
    Mart M Lamers; Jelte van der Vaart; Kèvin Knoops; Samra Riesebosch; Tim I Breugem; Anna Z Mykytyn; Joep Beumer; Debby Schipper; Karel Bezstarosti; Charlotte D Koopman; Nathalie Groen; Raimond B G Ravelli; Hans Q Duimel; Jeroen A A Demmers; Georges M G M Verjans; Marion P G Koopmans; Mauro J Muraro; Peter J Peters; Hans Clevers; Bart L Haagmans

    Severe acute respiratory syndrome coronavirus 2 (SARS‐CoV‐2) causes coronavirus disease 2019 (COVID‐19), which may result in acute respiratory distress syndrome (ARDS), multiorgan failure, and death. The alveolar epithelium is a major target of the virus, but representative models to study virus host interactions in more detail are currently lacking. Here, we describe a human 2D air–liquid interface

    更新日期:2021-01-11
  • Ythdf is a N6‐methyladenosine reader that modulates Fmr1 target mRNA selection and restricts axonal growth in Drosophila
    EMBO J. (IF 9.889) Pub Date : 2021-01-11
    Lina Worpenberg; Chiara Paolantoni; Sara Longhi; Miriam M Mulorz; Tina Lence; Hans‐Hermann Wessels; Erik Dassi; Giuseppe Aiello; F X Reymond Sutandy; Marion Scheibe; Raghu R Edupuganti; Anke Busch; Martin M Möckel; Michiel Vermeulen; Falk Butter; Julian König; Michela Notarangelo; Uwe Ohler; Christoph Dieterich; Alessandro Quattrone; Alessia Soldano; Jean‐Yves Roignant

    N6‐methyladenosine (m6A) regulates a variety of physiological processes through modulation of RNA metabolism. This modification is particularly enriched in the nervous system of several species, and its dysregulation has been associated with neurodevelopmental defects and neural dysfunctions. In Drosophila, loss of m6A alters fly behavior, albeit the underlying molecular mechanism and the role of m6A

    更新日期:2021-01-11
  • Crystal structure of bacterial cytotoxic necrotizing factor CNFY reveals molecular building blocks for intoxication
    EMBO J. (IF 9.889) Pub Date : 2021-01-07
    Paweena Chaoprasid; Peer Lukat; Sabrina Mühlen; Thomas Heidler; Emerich‐Mihai Gazdag; Shuangshuang Dong; Wenjie Bi; Christian Rüter; Marco Kirchenwitz; Anika Steffen; Lothar Jänsch; Theresia E B Stradal; Petra Dersch; Wulf Blankenfeldt

    Cytotoxic necrotizing factors (CNFs) are bacterial single‐chain exotoxins that modulate cytokinetic/oncogenic and inflammatory processes through activation of host cell Rho GTPases. To achieve this, they are secreted, bind surface receptors to induce endocytosis and translocate a catalytic unit into the cytosol to intoxicate host cells. A three‐dimensional structure that provides insight into the underlying

    更新日期:2021-01-07
  • ALK ligand ALKAL2 potentiates MYCN‐driven neuroblastoma in the absence of ALK mutation
    EMBO J. (IF 9.889) Pub Date : 2021-01-07
    Marcus Borenäs; Ganesh Umapathy; Wei‐Yun Lai; Dan E Lind; Barbara Witek; Jikui Guan; Patricia Mendoza‐Garcia; Tafheem Masudi; Arne Claeys; Tzu‐Po Chuang; Abeer El Wakil; Badrul Arefin; Susanne Fransson; Jan Koster; Mathias Johansson; Jennie Gaarder; Jimmy Van den Eynden; Bengt Hallberg; Ruth H Palmer

    High‐risk neuroblastoma (NB) is responsible for a disproportionate number of childhood deaths due to cancer. One indicator of high‐risk NB is amplification of the neural MYC (MYCN) oncogene, which is currently therapeutically intractable. Identification of anaplastic lymphoma kinase (ALK) as an NB oncogene raised the possibility of using ALK tyrosine kinase inhibitors (TKIs) in treatment of patients

    更新日期:2021-01-07
  • Best practices for the visualization, mapping, and manipulation of R‐loops
    EMBO J. (IF 9.889) Pub Date : 2021-01-07
    Frédéric Chédin; Stella R Hartono; Lionel A Sanz; Vincent Vanoosthuyse

    R‐loops represent an abundant class of large non‐B DNA structures in genomes. Even though they form transiently and at modest frequencies, interfering with R‐loop formation or dissolution has significant impacts on genome stability. Addressing the mechanism(s) of R‐loop‐mediated genome destabilization requires a precise characterization of their distribution in genomes. A number of independent methods

    更新日期:2021-01-07
  • Modulation of plant root growth by nitrogen source‐defined regulation of polar auxin transport
    EMBO J. (IF 9.889) Pub Date : 2021-01-05
    Krisztina Ötvös; Marco Marconi; Andrea Vega; Jose O’Brien; Alexander Johnson; Rashed Abualia; Livio Antonielli; Juan Carlos Montesinos; Yuzhou Zhang; Shutang Tan; Candela Cuesta; Christina Artner; Eleonore Bouguyon; Alain Gojon; Jirí Friml; Rodrigo A. Gutiérrez; Krzysztof Wabnik; Eva Benková

    Availability of the essential macronutrient nitrogen in soil plays a critical role in plant growth, development, and impacts agricultural productivity. Plants have evolved different strategies for sensing and responding to heterogeneous nitrogen distribution. Modulation of root system architecture, including primary root growth and branching, is among the most essential plant adaptions to ensure adequate

    更新日期:2021-01-05
  • Centrosome defects cause microcephaly by activating the 53BP1‐USP28‐TP53 mitotic surveillance pathway
    EMBO J. (IF 9.889) Pub Date : 2020-11-23
    Thao P Phan; Aubrey L Maryniak; Christina A Boatwright; Junsu Lee; Alisa Atkins; Andrea Tijhuis; Diana CJ Spierings; Hisham Bazzi; Floris Foijer; Philip W Jordan; Travis H Stracker; Andrew J Holland

    Mutations in centrosome genes deplete neural progenitor cells (NPCs) during brain development, causing microcephaly. While NPC attrition is linked to TP53‐mediated cell death in several microcephaly models, how TP53 is activated remains unclear. In cultured cells, mitotic delays resulting from centrosome loss prevent the growth of unfit daughter cells by activating a pathway involving 53BP1, USP28

    更新日期:2021-01-04
  • Flavonol‐mediated stabilization of PIN efflux complexes regulates polar auxin transport
    EMBO J. (IF 9.889) Pub Date : 2020-11-13
    William D Teale; Taras Pasternak; Cristina Dal Bosco; Alexander Dovzhenko; Krystyna Kratzat; Wolfgang Bildl; Manuel Schwörer; Thorsten Falk; Benadetto Ruperti; Jonas V Schaefer; Mojgan Shahriari; Lena Pilgermayer; Xugang Li; Florian Lübben; Andreas Plückthun; Uwe Schulte; Klaus Palme

    The transport of auxin controls the rate, direction and localization of plant growth and development. The course of auxin transport is defined by the polar subcellular localization of the PIN proteins, a family of auxin efflux transporters. However, little is known about the composition and regulation of the PIN protein complex. Here, using blue‐native PAGE and quantitative mass spectrometry, we identify

    更新日期:2021-01-04
  • Adjustment of the PIF7‐HFR1 transcriptional module activity controls plant shade adaptation
    EMBO J. (IF 9.889) Pub Date : 2020-12-02
    Sandi Paulišić; Wenting Qin; Harshul Arora Verasztó; Christiane Then; Benjamin Alary; Fabien Nogue; Miltos Tsiantis; Michael Hothorn; Jaime F Martínez‐García

    Shade caused by the proximity of neighboring vegetation triggers a set of acclimation responses to either avoid or tolerate shade. Comparative analyses between the shade‐avoider Arabidopsis thaliana and the shade‐tolerant Cardamine hirsuta revealed a role for the atypical basic‐helix‐loop‐helix LONG HYPOCOTYL IN FR 1 (HFR1) in maintaining the shade tolerance in C. hirsuta, inhibiting hypocotyl elongation

    更新日期:2021-01-04
  • Clustering and reverse transcription of HIV‐1 genomes in nuclear niches of macrophages
    EMBO J. (IF 9.889) Pub Date : 2020-12-03
    Elena Rensen; Florian Mueller; Viviana Scoca; Jyotsana J Parmar; Philippe Souque; Christophe Zimmer; Francesca Di Nunzio

    In order to replicate, human immunodeficiency virus (HIV‐1) reverse‐transcribes its RNA genome into DNA, which subsequently integrates into host cell chromosomes. These two key events of the viral life cycle are commonly viewed as separate not only in time, but also in cellular space, since reverse transcription (RT) is thought to be completed in the cytoplasm before nuclear import and integration

    更新日期:2021-01-04
  • Condensin minimizes topoisomerase II‐mediated entanglements of DNA in vivo
    EMBO J. (IF 9.889) Pub Date : 2020-11-06
    Sílvia Dyson; Joana Segura; Belén Martínez‐García; Antonio Valdés; Joaquim Roca

    The juxtaposition of intracellular DNA segments, together with the DNA‐passage activity of topoisomerase II, leads to the formation of DNA knots and interlinks, which jeopardize chromatin structure and gene expression. Recent studies in budding yeast have shown that some mechanism minimizes the knotting probability of intracellular DNA. Here, we tested whether this is achieved via the intrinsic capacity

    更新日期:2021-01-04
  • A structural inventory of native ribosomal ABCE1‐43S pre‐initiation complexes
    EMBO J. (IF 9.889) Pub Date : 2020-12-08
    Hanna Kratzat; Timur Mackens‐Kiani; Michael Ameismeier; Mia Potocnjak; Jingdong Cheng; Estelle Dacheux; Abdelkader Namane; Otto Berninghausen; Franz Herzog; Micheline Fromont‐Racine; Thomas Becker; Roland Beckmann

    In eukaryotic translation, termination and ribosome recycling phases are linked to subsequent initiation of a new round of translation by persistence of several factors at ribosomal sub‐complexes. These comprise/include the large eIF3 complex, eIF3j (Hcr1 in yeast) and the ATP‐binding cassette protein ABCE1 (Rli1 in yeast). The ATPase is mainly active as a recycling factor, but it can remain bound

    更新日期:2021-01-04
  • The high‐energy transition state of the glutamate transporter homologue GltPh
    EMBO J. (IF 9.889) Pub Date : 2020-11-13
    Gerard H M Huysmans; Didar Ciftci; Xiaoyu Wang; Scott C Blanchard; Olga Boudker

    Membrane transporters mediate cellular uptake of nutrients, signaling molecules, and drugs. Their overall mechanisms are often well understood, but the structural features setting their rates are mostly unknown. Earlier single‐molecule fluorescence imaging of the archaeal model glutamate transporter homologue GltPh from Pyrococcus horikoshii suggested that the slow conformational transition from the

    更新日期:2021-01-04
  • A non‐helical region in transmembrane helix 6 of hydrophobic amino acid transporter MhsT mediates substrate recognition
    EMBO J. (IF 9.889) Pub Date : 2020-11-06
    Dorota Focht; Caroline Neumann; Joseph Lyons; Ander Eguskiza Bilbao; Rickard Blunck; Lina Malinauskaite; Ilona O Schwarz; Jonathan A Javitch; Matthias Quick; Poul Nissen

    MhsT of Bacillus halodurans is a transporter of hydrophobic amino acids and a homologue of the eukaryotic SLC6 family of Na+‐dependent symporters for amino acids, neurotransmitters, osmolytes, or creatine. The broad range of transported amino acids by MhsT prompted the investigation of the substrate recognition mechanism. Here, we report six new substrate‐bound structures of MhsT, which, in conjunction

    更新日期:2021-01-04
  • Decreased blood vessel density and endothelial cell subset dynamics during ageing of the endocrine system
    EMBO J. (IF 9.889) Pub Date : 2020-11-20
    Junyu Chen; Luciana Lippo; Rossella Labella; Sin Lih Tan; Brian D Marsden; Michael L Dustin; Saravana K Ramasamy; Anjali P Kusumbe

    Age‐associated alterations of the hormone‐secreting endocrine system cause organ dysfunction and disease states. However, the cell biology of endocrine tissue ageing remains poorly understood. Here, we perform comparative 3D imaging to understand age‐related perturbations of the endothelial cell (EC) compartment in endocrine glands. Datasets of a wide range of markers highlight a decline in capillary

    更新日期:2021-01-04
  • Steroid‐dependent switch of OvoL/Shavenbaby controls self‐renewal versus differentiation of intestinal stem cells
    EMBO J. (IF 9.889) Pub Date : 2020-12-29
    Sandy Al Hayek; Ahmad Alsawadi; Zakaria Kambris; Jean‐Philippe Boquete; Jérôme Bohère; Clément Immarigeon; Brice Ronsin; Serge Plaza; Bruno Lemaitre; François Payre; Dani Osman

    Adult stem cells must continuously fine‐tune their behavior to regenerate damaged organs and avoid tumors. While several signaling pathways are well known to regulate somatic stem cells, the underlying mechanisms remain largely unexplored. Here, we demonstrate a cell‐intrinsic role for the OvoL family transcription factor, Shavenbaby (Svb), in balancing self‐renewal and differentiation of Drosophila

    更新日期:2020-12-29
  • Regulation of autophagosome biogenesis by OFD1‐mediated selective autophagy
    EMBO J. (IF 9.889) Pub Date : 2020-12-28
    Manuela Morleo; Simona Brillante; Umberto Formisano; Luigi Ferrante; Fabrizia Carbone; Daniela Iaconis; Alessandro Palma; Viviana Buonomo; Angela Serena Maione; Paolo Grumati; Carmine Settembre; Brunella Franco

    Autophagy is a lysosome‐dependent degradation pathway essential to maintain cellular homeostasis. Therefore, either defective or excessive autophagy may be detrimental for cells and tissues. The past decade was characterized by significant advances in molecular dissection of stimulatory autophagy inputs; however, our understanding of the mechanisms that restrain autophagy is far from complete. Here

    更新日期:2020-12-28
  • IFT54 directly interacts with kinesin‐II and IFT dynein to regulate anterograde intraflagellar transport
    EMBO J. (IF 9.889) Pub Date : 2020-12-28
    Xin Zhu; Jieling Wang; Shufen Li; Karl Lechtreck; Junmin Pan

    The intraflagellar transport (IFT) machinery consists of the anterograde motor kinesin‐II, the retrograde motor IFT dynein, and the IFT‐A and ‐B complexes. However, the interaction among IFT motors and IFT complexes during IFT remains elusive. Here, we show that the IFT‐B protein IFT54 interacts with both kinesin‐II and IFT dynein and regulates anterograde IFT. Deletion of residues 342–356 of Chlamydomonas

    更新日期:2020-12-28
  • hnRNPLL controls pluripotency exit of embryonic stem cells by modulating alternative splicing of Tbx3 and Bptf
    EMBO J. (IF 9.889) Pub Date : 2020-12-22
    Xue Wang; Changyun Ping; Puwen Tan; Chenguang Sun; Guang Liu; Tao Liu; Shuchun Yang; Yanmin Si; Lijun Zhao; Yongfei Hu; Yuyan Jia; Xiaoshuang Wang; Meili Zhang; Fang Wang; Dong Wang; Jia Yu; Yanni Ma; Yue Huang

    The regulatory circuitry underlying embryonic stem (ES) cell self‐renewal is well defined, but how this circuitry is disintegrated to enable lineage specification is unclear. RNA‐binding proteins (RBPs) have essential roles in RNA‐mediated gene regulation, and preliminary data suggest that they might regulate ES cell fate. By combining bioinformatic analyses with functional screening, we identified

    更新日期:2020-12-22
  • Tyrosine phosphorylation regulates hnRNPA2 granule protein partitioning and reduces neurodegeneration
    EMBO J. (IF 9.889) Pub Date : 2020-12-22
    Veronica H Ryan; Theodora M Perdikari; Mandar T Naik; Camillo F Saueressig; Jeremy Lins; Gregory L Dignon; Jeetain Mittal; Anne C Hart; Nicolas L Fawzi

    mRNA transport in neurons requires formation of transport granules containing many protein components, and subsequent alterations in phosphorylation status can release transcripts for translation. Further, mutations in a structurally disordered domain of the transport granule protein hnRNPA2 increase its aggregation and cause hereditary proteinopathy of neurons, myocytes, and bone. We examine in vitro

    更新日期:2020-12-22
  • ANKRD26 recruits PIDD1 to centriolar distal appendages to activate the PIDDosome following centrosome amplification
    EMBO J. (IF 9.889) Pub Date : 2020-12-22
    Lauren T Evans; Taylor Anglen; Phillip Scott; Kimberly Lukasik; Jadranka Loncarek; Andrew J Holland

    Centriole copy number is tightly maintained by the once‐per‐cycle duplication of these organelles. Centrioles constitute the core of centrosomes, which organize the microtubule cytoskeleton and form the poles of the mitotic spindle. Centrosome amplification is frequently observed in tumors, where it promotes aneuploidy and contributes to invasive phenotypes. In non‐transformed cells, centrosome amplification

    更新日期:2020-12-22
  • Centriolar distal appendages activate the centrosome‐PIDDosome‐p53 signalling axis via ANKRD26
    EMBO J. (IF 9.889) Pub Date : 2020-12-22
    Matteo Burigotto; Alessia Mattivi; Daniele Migliorati; Giovanni Magnani; Chiara Valentini; Michela Roccuzzo; Martin Offterdinger; Massimo Pizzato; Alexander Schmidt; Andreas Villunger; Stefano Maffini; Luca L Fava

    Centrosome amplification results into genetic instability and predisposes cells to neoplastic transformation. Supernumerary centrosomes trigger p53 stabilization dependent on the PIDDosome (a multiprotein complex composed by PIDD1, RAIDD and Caspase‐2), whose activation results in cleavage of p53’s key inhibitor, MDM2. Here, we demonstrate that PIDD1 is recruited to mature centrosomes by the centriolar

    更新日期:2020-12-22
  • Netrin‐1 and its receptor DCC modulate survival and death of dopamine neurons and Parkinson’s disease features
    EMBO J. (IF 9.889) Pub Date : 2020-12-22
    Mélissa Jasmin; Eun Hee Ahn; Merja H Voutilainen; Joanna Fombonne; Catherine Guix; Tuulikki Viljakainen; Seong Su Kang; Li‐ying Yu; Mart Saarma; Patrick Mehlen; Keqiang Ye

    The netrin‐1/DCC ligand/receptor pair has key roles in central nervous system (CNS) development, mediating axonal, and neuronal navigation. Although expression of netrin‐1 and DCC is maintained in the adult brain, little is known about their role in mature neurons. Notably, netrin‐1 is highly expressed in the adult substantia nigra, leading us to investigate a role of the netrin‐1/DCC pair in adult

    更新日期:2020-12-22
  • A sensory cell diversifies its output by varying Ca2+ influx‐release coupling among active zones
    EMBO J. (IF 9.889) Pub Date : 2020-12-21
    Özge D Özçete; Tobias Moser

    The cochlea encodes sound pressures varying over six orders of magnitude by collective operation of functionally diverse spiral ganglion neurons (SGNs). The mechanisms enabling this functional diversity remain elusive. Here, we asked whether the sound intensity information, contained in the receptor potential of the presynaptic inner hair cell (IHC), is fractionated via heterogeneous synapses. We studied

    更新日期:2020-12-21
  • Clock component OsPRR73 positively regulates rice salt tolerance by modulating OsHKT2;1‐mediated sodium homeostasis
    EMBO J. (IF 9.889) Pub Date : 2020-12-21
    Hua Wei; Xiling Wang; Yuqing He; Hang Xu; Lei Wang

    The roles of clock components in salt stress tolerance remain incompletely characterized in rice. Here, we show that, among OsPRR (Oryza sativa Pseudo‐Response Regulator) family members, OsPRR73 specifically confers salt tolerance in rice. Notably, the grain size and yield of osprr73 null mutants were significantly decreased in the presence of salt stress, with accumulated higher level of reactive

    更新日期:2020-12-21
  • Direct interaction of β‐catenin with nuclear ESM1 supports stemness of metastatic prostate cancer
    EMBO J. (IF 9.889) Pub Date : 2020-12-21
    Ke‐Fan Pan; Wei‐Jiunn Lee; Chun‐Chi Chou; Yi‐Chieh Yang; Yu‐Chan Chang; Ming‐Hsien Chien; Michael Hsiao; Kuo‐Tai Hua

    Wnt/β‐catenin signaling is frequently activated in advanced prostate cancer and contributes to therapy resistance and metastasis. However, activating mutations in the Wnt/β‐catenin pathway are not common in prostate cancer, suggesting alternative regulations may exist. Here, we report that the expression of endothelial cell‐specific molecule 1 (ESM1), a secretory proteoglycan, is positively associated

    更新日期:2020-12-21
  • Opposing activities of IFITM proteins in SARS‐CoV‐2 infection
    EMBO J. (IF 9.889) Pub Date : 2020-12-21
    Guoli Shi; Adam D Kenney; Elena Kudryashova; Ashley Zani; Lizhi Zhang; Kin Kui Lai; Luanne Hall‐Stoodley; Richard T Robinson; Dmitri S Kudryashov; Alex A Compton; Jacob S Yount

    Interferon‐induced transmembrane proteins (IFITMs) restrict infections by many viruses, but a subset of IFITMs enhance infections by specific coronaviruses through currently unknown mechanisms. We show that SARS‐CoV‐2 Spike‐pseudotyped virus and genuine SARS‐CoV‐2 infections are generally restricted by human and mouse IFITM1, IFITM2, and IFITM3, using gain‐ and loss‐of‐function approaches. Mechanistically

    更新日期:2020-12-21
  • Integrator is recruited to promoter‐proximally paused RNA Pol II to generate Caenorhabditis elegans piRNA precursors
    EMBO J. (IF 9.889) Pub Date : 2020-12-19
    Toni Beltran; Elena Pahita; Subhanita Ghosh; Boris Lenhard; Peter Sarkies

    Piwi‐interacting RNAs (piRNAs) play key roles in germline development and genome defence in metazoans. In C. elegans, piRNAs are transcribed from > 15,000 discrete genomic loci by RNA polymerase II (Pol II), resulting in 28 nt short‐capped piRNA precursors. Here, we investigate transcription termination at piRNA loci. We show that the Integrator complex, which terminates snRNA transcription, is recruited

    更新日期:2020-12-20
  • SATB2‐LEMD2 interaction links nuclear shape plasticity to regulation of cognition‐related genes
    EMBO J. (IF 9.889) Pub Date : 2020-12-15
    Patrick Feurle; Andreas Abentung; Isabella Cera; Nico Wahl; Cornelia Ablinger; Michael Bucher; Eduard Stefan; Simon Sprenger; David Teis; Andre Fischer; Aodán Laighneach; Laura Whitton; Derek W Morris; Galina Apostolova; Georg Dechant

    SATB2 is a schizophrenia risk gene and is genetically associated with human intelligence. How it affects cognition at molecular level is currently unknown. Here, we show that interactions between SATB2, a chromosomal scaffolding protein, and the inner nuclear membrane protein LEMD2 orchestrate the response of pyramidal neurons to neuronal activation. Exposure to novel environment in vivo causes changes

    更新日期:2020-12-15
  • Modulation of Yorkie activity by alternative splicing is required for developmental stability
    EMBO J. (IF 9.889) Pub Date : 2020-12-15
    Diwas Srivastava; Marion de Toledo; Laurent Manchon; Jamal Tazi; François Juge

    The Hippo signaling pathway is a major regulator of organ growth, which controls the activity of the transcription coactivator Yorkie (Yki) in Drosophila and its homolog YAP in mammals. Both Yki and YAP proteins exist as alternatively spliced isoforms containing either one or two WW domains. The biological importance of this conserved alternative splicing event is unknown. Here, we identify the splicing

    更新日期:2020-12-15
  • The last wall of defense to prevent extreme and deleterious mitochondrial fusion
    EMBO J. (IF 9.889) Pub Date : 2020-12-09
    Luis Carlos Tábara; Julien Prudent

    Mitochondria are dynamic organelles adapting their morphology by cycles of fission and fusion events to control cellular homeostasis. In this issue of The EMBO Journal, Murata and colleagues (2020) show that lack of mitochondrial division leads to safeguard mechanisms, induced by transient mitochondrial membrane depolarization and activation of the metalloprotease OMA1, to prevent extreme mitochondrial

    更新日期:2020-12-15
  • Rebellious autophagy proteins bypass ATG8 lipidation, taking their own path to autophagic degradation
    EMBO J. (IF 9.889) Pub Date : 2020-11-23
    Thanh Ngoc Nguyen; Michael Lazarou

    LC3/GABARAP (hereafter ATG8) conjugation machineries have long been thought to play an essential role in autophagy by driving ATG8 lipidation on autophagosomal membranes. In this issue, Ohnstad et al (2020) describe an ATG8 lipidation bypass pathway which governs autophagy‐dependent turnover of NBR1, highlighting that there is more than one road to autophagic degradation.

    更新日期:2020-12-15
  • Immune subversion by HIV: part B
    EMBO J. (IF 9.889) Pub Date : 2020-12-08
    Christophe Vanpouille; Leonid Margolis

    While HIV‐1 infects T but not B cells, it nevertheless impairs the function of B cells and thereby contribute to the failure to produce neutralizing antibodies. In this issue, Kaw et al describe the mechanisms leading to this failure and report a key role for the HIV‐1 protein NEF in preventing B‐cell maturation into antibody‐producing plasma cells.

    更新日期:2020-12-15
  • Structure and elevator mechanism of the mammalian sodium/proton exchanger NHE9
    EMBO J. (IF 9.889) Pub Date : 2020-10-29
    Iven Winklemann; Rei Matsuoka; Pascal F Meier; Denis Shutin; Chenou Zhang; Laura Orellana; Ricky Sexton; Michael Landreh; Carol V Robinson; Oliver Beckstein; David Drew

    Na+/H+ exchangers (NHEs) are ancient membrane‐bound nanomachines that work to regulate intracellular pH, sodium levels and cell volume. NHE activities contribute to the control of the cell cycle, cell proliferation, cell migration and vesicle trafficking. NHE dysfunction has been linked to many diseases, and they are targets of pharmaceutical drugs. Despite their fundamental importance to cell homeostasis

    更新日期:2020-12-15
  • Mitochondrial Safeguard: a stress response that offsets extreme fusion and protects respiratory function via flickering‐induced Oma1 activation
    EMBO J. (IF 9.889) Pub Date : 2020-11-17
    Daisuke Murata; Tatsuya Yamada; Takeshi Tokuyama; Kenta Arai; Pedro M Quirós; Carlos López‐Otín; Miho Iijima; Hiromi Sesaki

    The connectivity of mitochondria is regulated by a balance between fusion and division. Many human diseases are associated with excessive mitochondrial connectivity due to impaired Drp1, a dynamin‐related GTPase that mediates division. Here, we report a mitochondrial stress response, named mitochondrial safeguard, that adjusts the balance of fusion and division in response to increased mitochondrial

    更新日期:2020-12-15
  • Receptor‐mediated clustering of FIP200 bypasses the role of LC3 lipidation in autophagy
    EMBO J. (IF 9.889) Pub Date : 2020-11-23
    Amelia E Ohnstad; Jose M Delgado; Brian J North; Isha Nasa; Arminja N Kettenbach; Sebastian W Schultz; Christopher J Shoemaker

    Autophagosome formation requires multiple autophagy‐related (ATG) factors. However, we find that a subset of autophagy substrates remains robustly targeted to the lysosome in the absence of several core ATGs, including the LC3 lipidation machinery. To address this unexpected result, we performed genome‐wide CRISPR screens identifying genes required for NBR1 flux in ATG7KO cells. We find that ATG7‐independent

    更新日期:2020-12-15
  • HIV‐1 infection of CD4 T cells impairs antigen‐specific B cell function
    EMBO J. (IF 9.889) Pub Date : 2020-11-04
    Sheetal Kaw; Swetha Ananth; Nikolaos Tsopoulidis; Katharina Morath; Bahar M Coban; Ralph Hohenberger; Olcay C Bulut; Florian Klein; Bettina Stolp; Oliver T Fackler

    Failures to produce neutralizing antibodies upon HIV‐1 infection result in part from B‐cell dysfunction due to unspecific B‐cell activation. How HIV‐1 affects antigen‐specific B‐cell functions remains elusive. Using an adoptive transfer mouse model and ex vivo HIV infection of human tonsil tissue, we found that expression of the HIV‐1 pathogenesis factor NEF in CD4 T cells undermines their helper function

    更新日期:2020-12-15
  • Blood molecular markers associated with COVID‐19 immunopathology and multi‐organ damage
    EMBO J. (IF 9.889) Pub Date : 2020-12-14
    Yan‐Mei Chen; Yuanting Zheng; Ying Yu; Yunzhi Wang; Qingxia Huang; Feng Qian; Lei Sun; Zhi‐Gang Song; Ziyin Chen; Jinwen Feng; Yanpeng An; Jingcheng Yang; Zhenqiang Su; Shanyue Sun; Fahui Dai; Qinsheng Chen; Qinwei Lu; Pengcheng Li; Yun Ling; Zhong Yang; Huiru Tang; Leming Shi; Li Jin; Edward C Holmes; Chen Ding; Tong‐Yu Zhu; Yong‐Zhen Zhang

    COVID‐19 is characterized by dysregulated immune responses, metabolic dysfunction and adverse effects on the function of multiple organs. To understand host responses to COVID‐19 pathophysiology, we combined transcriptomics, proteomics, and metabolomics to identify molecular markers in peripheral blood and plasma samples of 66 COVID‐19‐infected patients experiencing a range of disease severities and

    更新日期:2020-12-15