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  • Molecular flexibility of DNA as a key determinant of RAD51 recruitment
    EMBO J. (IF 11.227) Pub Date : 2020-01-14
    Federico Paoletti; Afaf H El‐Sagheer; Jun Allard; Tom Brown; Omer Dushek; Fumiko Esashi

    The timely activation of homologous recombination is essential for the maintenance of genome stability, in which the RAD51 recombinase plays a central role. Biochemically, human RAD51 polymerises faster on single‐stranded DNA (ssDNA) compared to double‐stranded DNA (dsDNA), raising a key conceptual question: how does it discriminate between them? In this study, we tackled this problem by systematically assessing RAD51 binding kinetics on ssDNA and dsDNA differing in length and flexibility using surface plasmon resonance. By directly fitting a mechanistic model to our experimental data, we demonstrate that the RAD51 polymerisation rate positively correlates with the flexibility of DNA. Once the RAD51‐DNA complex is formed, however, RAD51 remains stably bound independent of DNA flexibility, but rapidly dissociates from flexible DNA when RAD51 self‐association is perturbed. This model presents a new general framework suggesting that the flexibility of DNA, which may increase locally as a result of DNA damage, plays an important role in rapidly recruiting repair factors that multimerise at sites of DNA damage.

    更新日期:2020-01-15
  • Generation of a self‐cleaved inducible Cre recombinase for efficient temporal genetic manipulation
    EMBO J. (IF 11.227) Pub Date : 2020-01-14
    Xueying Tian; Lingjuan He; Kuo Liu; Wenjuan Pu; Huan Zhao; Yan Li; Xiuxiu Liu; Muxue Tang; Ruilin Sun; Jian Fei; Yong Ji; Zengyong Qiao; Kathy O Lui; Bin Zhou

    Site‐specific recombinase‐mediated genetic technology, such as inducible Cre‐loxP recombination (CreER), is widely used for in vivo genetic manipulation with temporal control. The Cre‐loxP technology improves our understanding on the in vivo function of specific genes in organ development, tissue regeneration, and disease progression. However, inducible CreER often remains inefficient in gene deletion. In order to improve the efficiency of gene manipulation, we generated a self‐cleaved inducible CreER (sCreER) that switches inducible CreER into a constitutively active Cre by itself. We generated endocardial driver Npr3‐sCreER and fibroblast driver Col1a2‐sCreER, and compared them with conventional Npr3‐CreER and Col1a2‐CreER, respectively. For easy‐to‐recombine alleles such as R26‐tdTomato, there was no significant difference in recombination efficiency between sCreER and the conventional CreER. However, for alleles that were relatively inert for recombination such as R26‐Confetti, R26‐LZLT, R26‐GFP, or VEGFR2flox/flox alleles, sCreER showed a significantly higher efficiency in recombination compared with conventional CreER in endocardial cells or fibroblasts. Compared with conventional CreER, sCreER significantly enhances the efficiency of recombination to induce gene expression or gene deletion, allowing temporal yet effective in vivo genomic modification for studying gene function in specific cell lineages.

    更新日期:2020-01-14
  • Reduced autophagy upon C9ORF72 loss synergizes with dipeptide repeat protein toxicity in G4C2 repeat expansion disorders
    EMBO J. (IF 11.227) Pub Date : 2020-01-13
    Manon Boivin; Véronique Pfister; Angeline Gaucherot; Frank Ruffenach; Luc Negroni; Chantal Sellier; Nicolas Charlet‐Berguerand

    Expansion of G4C2 repeats within the C9ORF72 gene is the most common cause of amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). Such repeats lead to decreased expression of the autophagy regulator C9ORF72 protein. Furthermore, sense and antisense repeats are translated into toxic dipeptide repeat (DPR) proteins. It is unclear how these repeats are translated, and in which way their translation and the reduced expression of C9ORF72 modulate repeat toxicity. Here, we found that sense and antisense repeats are translated upon initiation at canonical AUG or near‐cognate start codons, resulting in polyGA‐, polyPG‐, and to a lesser degree polyGR‐DPR proteins. However, accumulation of these proteins is prevented by autophagy. Importantly, reduced C9ORF72 levels lead to suboptimal autophagy, thereby impairing clearance of DPR proteins and causing their toxic accumulation, ultimately resulting in neuronal cell death. Of clinical importance, pharmacological compounds activating autophagy can prevent neuronal cell death caused by DPR proteins accumulation. These results suggest the existence of a double‐hit pathogenic mechanism in ALS/FTD, whereby reduced expression of C9ORF72 synergizes with DPR protein accumulation and toxicity.

    更新日期:2020-01-14
  • In situ CRISPR‐Cas9 base editing for the development of genetically engineered mouse models of breast cancer
    EMBO J. (IF 11.227) Pub Date : 2020-01-13
    Stefano Annunziato; Catrin Lutz; Linda Henneman; Jinhyuk Bhin; Kim Wong; Bjørn Siteur; Bas van Gerwen; Renske de Korte‐Grimmerink; Maria Paz Zafra; Emma M Schatoff; Anne Paulien Drenth; Eline van der Burg; Timo Eijkman; Siddhartha Mukherjee; Katharina Boroviak; Lodewyk FA Wessels; Marieke van de Ven; Ivo J Huijbers; David J Adams; Lukas E Dow; Jos Jonkers

    Genetically engineered mouse models (GEMMs) of cancer have proven to be of great value for basic and translational research. Although CRISPR‐based gene disruption offers a fast‐track approach for perturbing gene function and circumvents certain limitations of standard GEMM development, it does not provide a flexible platform for recapitulating clinically relevant missense mutations in vivo. To this end, we generated knock‐in mice with Cre‐conditional expression of a cytidine base editor and tested their utility for precise somatic engineering of missense mutations in key cancer drivers. Upon intraductal delivery of sgRNA‐encoding vectors, we could install point mutations with high efficiency in one or multiple endogenous genes in situ and assess the effect of defined allelic variants on mammary tumorigenesis. While the system also produces bystander insertions and deletions that can stochastically be selected for when targeting a tumor suppressor gene, we could effectively recapitulate oncogenic nonsense mutations. We successfully applied this system in a model of triple‐negative breast cancer, providing the proof of concept for extending this flexible somatic base editing platform to other tissues and tumor types.

    更新日期:2020-01-14
  • FAM134B oligomerization drives endoplasmic reticulum membrane scission for ER‐phagy
    EMBO J. (IF 11.227) Pub Date : 2020-01-13
    Xiao Jiang; Xinyi Wang; Xianming Ding; Mengjie Du; Boran Li; Xialian Weng; Jingzi Zhang; Lin Li; Rui Tian; Qi Zhu; She Chen; Liang Wang; Wei Liu; Lei Fang; Dante Neculai; Qiming Sun

    Degradation of endoplasmic reticulum (ER) by selective autophagy (ER‐phagy) is crucial for ER homeostasis. However, it remains unclear how ER scission is regulated for subsequent autophagosomal sequestration and lysosomal degradation. Here, we show that oligomerization of ER‐phagy receptor FAM134B (also referred to as reticulophagy regulator 1 or RETREG1) through its reticulon‐homology domain is required for membrane fragmentation in vitro and ER‐phagy in vivo. Under ER‐stress conditions, activated CAMK2B phosphorylates the reticulon‐homology domain of FAM134B, which enhances FAM134B oligomerization and activity in membrane fragmentation to accommodate high demand for ER‐phagy. Unexpectedly, FAM134B G216R, a variant derived from a type II hereditary sensory and autonomic neuropathy (HSAN) patient, exhibits gain‐of‐function defects, such as hyperactive self‐association and membrane scission, which results in excessive ER‐phagy and sensory neuron death. Therefore, this study reveals a mechanism of ER membrane fragmentation in ER‐phagy, along with a signaling pathway in regulating ER turnover, and suggests a potential implication of excessive selective autophagy in human diseases.

    更新日期:2020-01-14
  • Rhomboid intramembrane protease YqgP licenses bacterial membrane protein quality control as adaptor of FtsH AAA protease
    EMBO J. (IF 11.227) Pub Date : 2020-01-13
    Jakub Began; Baptiste Cordier; Jana Březinová; Jordan Delisle; Rozálie Hexnerová; Pavel Srb; Petra Rampírová; Milan Kožíšek; Mathieu Baudet; Yohann Couté; Anne Galinier; Václav Veverka; Thierry Doan; Kvido Strisovsky

    Magnesium homeostasis is essential for life and depends on magnesium transporters, whose activity and ion selectivity need to be tightly controlled. Rhomboid intramembrane proteases pervade the prokaryotic kingdom, but their functions are largely elusive. Using proteomics, we find that Bacillus subtilis rhomboid protease YqgP interacts with the membrane‐bound ATP‐dependent processive metalloprotease FtsH and cleaves MgtE, the major high‐affinity magnesium transporter in B. subtilis. MgtE cleavage by YqgP is potentiated in conditions of low magnesium and high manganese or zinc, thereby protecting B. subtilis from Mn2+/Zn2+ toxicity. The N‐terminal cytosolic domain of YqgP binds Mn2+ and Zn2+ ions and facilitates MgtE cleavage. Independently of its intrinsic protease activity, YqgP acts as a substrate adaptor for FtsH, a function that is necessary for degradation of MgtE. YqgP thus unites protease and pseudoprotease function, hinting at the evolutionary origin of rhomboid pseudoproteases such as Derlins that are intimately involved in eukaryotic ER‐associated degradation (ERAD). Conceptually, the YqgP‐FtsH system we describe here is analogous to a primordial form of “ERAD” in bacteria and exemplifies an ancestral function of rhomboid‐superfamily proteins.

    更新日期:2020-01-14
  • Autophagy mediates temporary reprogramming and dedifferentiation in plant somatic cells
    EMBO J. (IF 11.227) Pub Date : 2020-01-13
    Eleazar Rodriguez; Jonathan Chevalier; Jakob Olsen; Jeppe Ansbøl; Vaitsa Kapousidou; Zhangli Zuo; Steingrim Svenning; Christian Loefke; Stefanie Koemeda; Pedro Serrano Drozdowskyj; Jakub Jez; Gerhard Durnberger; Fabian Kuenzl; Michael Schutzbier; Karl Mechtler; Elise Nagel Ebstrup; Signe Lolle; Yasin Dagdas; Morten Petersen

    Somatic cells acclimate to changes in the environment by temporary reprogramming. Much has been learned about transcription factors that induce these cell‐state switches in both plants and animals, but how cells rapidly modulate their proteome remains elusive. Here, we show rapid induction of autophagy during temporary reprogramming in plants triggered by phytohormones, immune, and danger signals. Quantitative proteomics following sequential reprogramming revealed that autophagy is required for timely decay of previous cellular states and for tweaking the proteome to acclimate to the new conditions. Signatures of previous cellular programs thus persist in autophagy‐deficient cells, affecting cellular decision‐making. Concordantly, autophagy‐deficient cells fail to acclimatize to dynamic climate changes. Similarly, they have defects in dedifferentiating into pluripotent stem cells, and redifferentiation during organogenesis. These observations indicate that autophagy mediates cell‐state switches that underlie somatic cell reprogramming in plants and possibly other organisms, and thereby promotes phenotypic plasticity.

    更新日期:2020-01-14
  • Adipocyte extracellular vesicles carry enzymes and fatty acids that stimulate mitochondrial metabolism and remodeling in tumor cells
    EMBO J. (IF 11.227) Pub Date : 2020-01-10
    Emily Clement; Ikrame Lazar; Camille Attané; Lorry Carrié; Stéphanie Dauvillier; Manuelle Ducoux‐Petit; David Esteve; Thomas Menneteau; Mohamed Moutahir; Sophie Le Gonidec; Stéphane Dalle; Philippe Valet; Odile Burlet‐Schiltz; Catherine Muller; Laurence Nieto

    Extracellular vesicles are emerging key actors in adipocyte communication. Notably, small extracellular vesicles shed by adipocytes stimulate fatty acid oxidation and migration in melanoma cells and these effects are enhanced in obesity. However, the vesicular actors and cellular processes involved remain largely unknown. Here, we elucidate the mechanisms linking adipocyte extracellular vesicles to metabolic remodeling and cell migration. We show that adipocyte vesicles stimulate melanoma fatty acid oxidation by providing both enzymes and substrates. In obesity, the heightened effect of extracellular vesicles depends on increased transport of fatty acids, not fatty acid oxidation‐related enzymes. These fatty acids, stored within lipid droplets in cancer cells, drive fatty acid oxidation upon being released by lipophagy. This increase in mitochondrial activity redistributes mitochondria to membrane protrusions of migrating cells, which is necessary to increase cell migration in the presence of adipocyte vesicles. Our results provide key insights into the role of extracellular vesicles in the metabolic cooperation that takes place between adipocytes and tumors with particular relevance to obesity.

    更新日期:2020-01-10
  • Tyrosine phosphorylation of the lectin receptor‐like kinase LORE regulates plant immunity
    EMBO J. (IF 11.227) Pub Date : 2020-01-10
    Xuming Luo; Wei Wu; Yingbo Liang; Ning Xu; Zongyi Wang; Huasong Zou; Jun Liu

    Plant pattern recognition receptors (PRRs) perceive pathogen‐associated molecular patterns (PAMPs) to activate immune responses. Medium‐chain 3‐hydroxy fatty acids (mc‐3‐OH‐FAs), which are widely present in Gram‐negative bacteria, were recently shown to be novel PAMPs in Arabidopsis thaliana. The Arabidopsis PRR LIPOOLIGOSACCHARIDE‐SPECIFIC REDUCED ELICITATION (LORE) is a G‐type lectin receptor‐like kinase that recognizes mc‐3‐OH‐FAs and subsequently mounts an immune response; however, the mechanisms underlying LORE activation and downstream signaling are unexplored. Here, we report that one of the mc‐3‐OH‐FAs, 3‐OH‐C10:0, induces phosphorylation of LORE at tyrosine residue 600 (Y600). Phosphorylated LORE subsequently trans‐phosphorylates the receptor‐like cytoplasmic kinase PBL34 and its close paralogs, PBL35 and PBL36, and therefore activates plant immunity. Phosphorylation of LORE Y600 is required for downstream phosphorylation of PBL34, PBL35, and PBL36. However, the Pseudomonas syringae effector HopAO1 targets LORE, dephosphorylating the tyrosine‐phosphorylated Y600 and therefore suppressing the immune response. These observations uncover the mechanism by which LORE mediates signaling in response to 3‐OH‐C10:0 in Arabidopsis.

    更新日期:2020-01-10
  • The heat's on: nuclear stress bodies signal intron retention
    EMBO J. (IF 11.227) Pub Date : 2020-01-09
    Sylvia Erhardt; Georg Stoecklin

    The cellular response to heat shock requires massive adaptation of gene expression driven by the transcription factor HSF1, which assembles in nuclear stress bodies together with human satellite III RNA and numerous splicing factors. In this issue of The EMBO Journal, Ninomiya et al demonstrate that nuclear stress bodies serve as a platform for phosphorylation of the SR protein SRSF9 by the CLK1 kinase, which promotes retention of a large number of introns during the recovery phase from heat shock.

    更新日期:2020-01-10
  • Respiratory supercomplexes act as a platform for complex III‐mediated maturation of human mitochondrial complexes I and IV
    EMBO J. (IF 11.227) Pub Date : 2020-01-08
    Margherita Protasoni; Rafael Pérez‐Pérez; Teresa Lobo‐Jarne; Michael E Harbour; Shujing Ding; Ana Peñas; Francisca Diaz; Carlos T Moraes; Ian M Fearnley; Massimo Zeviani; Cristina Ugalde; Erika Fernández‐Vizarra

    Mitochondrial respiratory chain (MRC) enzymes associate in supercomplexes (SCs) that are structurally interdependent. This may explain why defects in a single component often produce combined enzyme deficiencies in patients. A case in point is the alleged destabilization of complex I in the absence of complex III. To clarify the structural and functional relationships between complexes, we have used comprehensive proteomic, functional, and biogenetical approaches to analyze a MT‐CYB‐deficient human cell line. We show that the absence of complex III blocks complex I biogenesis by preventing the incorporation of the NADH module rather than decreasing its stability. In addition, complex IV subunits appeared sequestered within complex III subassemblies, leading to defective complex IV assembly as well. Therefore, we propose that complex III is central for MRC maturation and SC formation. Our results challenge the notion that SC biogenesis requires the pre‐formation of fully assembled individual complexes. In contrast, they support a cooperative‐assembly model in which the main role of complex III in SCs is to provide a structural and functional platform for the completion of overall MRC biogenesis.

    更新日期:2020-01-08
  • RNA toxicity in non‐coding repeat expansion disorders
    EMBO J. (IF 11.227) Pub Date : 2019-11-13
    Bart Swinnen; Wim Robberecht; Ludo Van Den Bosch

    Several neurodegenerative disorders like amyotrophic lateral sclerosis (ALS) and spinocerebellar ataxia (SCA) are caused by non‐coding nucleotide repeat expansions. Different pathogenic mechanisms may underlie these non‐coding repeat expansion disorders. While gain‐of‐function mechanisms, such as toxicity associated with expression of repeat RNA or toxicity associated with repeat‐associated non‐ATG (RAN) products, are most frequently connected with these disorders, loss‐of‐function mechanisms have also been implicated. We review the different pathways that have been linked to non‐coding repeat expansion disorders such as C9ORF72‐linked ALS/frontotemporal dementia (FTD), myotonic dystrophy, fragile X tremor/ataxia syndrome (FXTAS), SCA, and Huntington's disease‐like 2. We discuss modes of RNA toxicity focusing on the identity and the interacting partners of the toxic RNA species. Using the C9ORF72 ALS/FTD paradigm, we further explore the efforts and different methods used to disentangle RNA vs. RAN toxicity. Overall, we conclude that there is ample evidence for a role of RNA toxicity in non‐coding repeat expansion diseases.

    更新日期:2020-01-02
  • Paracaspase MALT1 regulates glioma cell survival by controlling endo‐lysosome homeostasis
    EMBO J. (IF 11.227) Pub Date : 2019-11-27
    Kathryn A Jacobs; Gwennan André‐Grégoire; Clément Maghe; An Thys; Ying Li; Elizabeth Harford‐Wright; Kilian Trillet; Tiphaine Douanne; Carolina Alves Nicolau; Jean‐Sébastien Frénel; Nicolas Bidère; Julie Gavard
    更新日期:2020-01-02
  • Life‐long impairment of glucose homeostasis upon prenatal exposure to psychostimulants
    EMBO J. (IF 11.227) Pub Date : 2019-11-21
    Solomiia Korchynska; Maria Krassnitzer; Katarzyna Malenczyk; Rashmi B Prasad; Evgenii O Tretiakov; Sabah Rehman; Valentina Cinquina; Victoria Gernedl; Matthias Farlik; Julian Petersen; Sophia Hannes; Julia Schachenhofer; Sonali N Reisinger; Alice Zambon; Olof Asplund; Isabella Artner; Erik Keimpema; Gert Lubec; Jan Mulder; Christoph Bock; Daniela D Pollak; Roman A Romanov; Christian Pifl; Leif Groop; Tomas GM Hökfelt; Tibor Harkany
    更新日期:2020-01-02
  • Kinesin Kif3b mutation reduces NMDAR subunit NR2A trafficking and causes schizophrenia‐like phenotypes in mice
    EMBO J. (IF 11.227) Pub Date : 2019-11-20
    Ashwaq Hassan Alsabban; Momo Morikawa; Yosuke Tanaka; Yosuke Takei; Nobutaka Hirokawa
    更新日期:2020-01-02
  • Non‐canonical AUX/IAA protein IAA33 competes with canonical AUX/IAA repressor IAA5 to negatively regulate auxin signaling
    EMBO J. (IF 11.227) Pub Date : 2019-10-16
    Bingsheng Lv; Qianqian Yu; Jiajia Liu; Xuejing Wen; Zhenwei Yan; Kongqin Hu; Hanbing Li; Xiangpei Kong; Cuiling Li; Huiyu Tian; Ive De Smet; Xian‐Sheng Zhang; Zhaojun Ding
    更新日期:2020-01-02
  • Elucidation of WW domain ligand binding specificities in the Hippo pathway reveals STXBP4 as YAP inhibitor
    EMBO J. (IF 11.227) Pub Date : 2019-11-29
    Rebecca E Vargas; Vy Thuy Duong; Han Han; Albert Paul Ta; Yuxuan Chen; Shiji Zhao; Bing Yang; Gayoung Seo; Kimberly Chuc; Sunwoo Oh; Amal El Ali; Olga V Razorenova; Junjie Chen; Ray Luo; Xu Li; Wenqi Wang
    更新日期:2020-01-02
  • Heterochromatin loosening by the Oct4 linker region facilitates Klf4 binding and iPSC reprogramming
    EMBO J. (IF 11.227) Pub Date : 2019-10-01
    Keshi Chen; Qi Long; Guangsuo Xing; Tianyu Wang; Yi Wu; Linpeng Li; Juntao Qi; Yanshuang Zhou; Bochao Ma; Hans R Schöler; Jinfu Nie; Duanqing Pei; Xingguo Liu
    更新日期:2020-01-02
  • Nipped‐A regulates the Drosophila circadian clock via histone deubiquitination
    EMBO J. (IF 11.227) Pub Date : 2019-09-19
    Bei Bu; Lixia Chen; Liubin Zheng; Weiwei He; Luoying Zhang
    更新日期:2020-01-02
  • Distinct IL‐1α‐responsive enhancers promote acute and coordinated changes in chromatin topology in a hierarchical manner
    EMBO J. (IF 11.227) Pub Date : 2019-11-07
    Sinah‐Sophia Weiterer; Johanna Meier‐Soelch; Theodore Georgomanolis; Athanasia Mizi; Anna Beyerlein; Hendrik Weiser; Lilija Brant; Christin Mayr‐Buro; Liane Jurida; Knut Beuerlein; Helmut Müller; Axel Weber; Ulas Tenekeci; Oliver Dittrich‐Breiholz; Marek Bartkuhn; Andrea Nist; Thorsten Stiewe; Wilfred FJ van IJcken; Tabea Riedlinger; M Lienhard Schmitz; Argyris Papantonis; Michael Kracht
    更新日期:2020-01-02
  • Biologically indeterminate yet ordered promiscuous gene expression in single medullary thymic epithelial cells
    EMBO J. (IF 11.227) Pub Date : 2019-10-28
    Fatima Dhalla; Jeanette Baran‐Gale; Stefano Maio; Lia Chappell; Georg A Holländer; Chris P Ponting
    更新日期:2020-01-02
  • Micropeptide CIP2A‐BP encoded by LINC00665 inhibits triple‐negative breast cancer progression
    EMBO J. (IF 11.227) Pub Date : 2019-11-22
    Binbin Guo; Siqi Wu; Xun Zhu; Liyuan Zhang; Jieqiong Deng; Fang Li; Yirong Wang; Shenghua Zhang; Rui Wu; Jiachun Lu; Yifeng Zhou
    更新日期:2020-01-02
  • RanGTP and importin β regulate meiosis I spindle assembly and function in mouse oocytes
    EMBO J. (IF 11.227) Pub Date : 2019-10-16
    David Drutovic; Xing Duan; Rong Li; Petr Kalab; Petr Solc
    更新日期:2020-01-02
  • Cytoskeletal tension actively sustains the migratory T‐cell synaptic contact
    EMBO J. (IF 11.227) Pub Date : 2020-01-02
    Sudha Kumari; Michael Mak; Yeh‐Chuin Poh; Mira Tohme; Nicki Watson; Mariane Melo; Erin Janssen; Michael Dustin; Raif Geha; Darrell J Irvine

    When migratory T cells encounter antigen‐presenting cells (APCs), they arrest and form radially symmetric, stable intercellular junctions termed immunological synapses which facilitate exchange of crucial biochemical information and are critical for T‐cell immunity. While the cellular processes underlying synapse formation have been well characterized, those that maintain the symmetry, and thereby the stability of the synapse, remain unknown. Here we identify an antigen‐triggered mechanism that actively promotes T‐cell synapse symmetry by generating cytoskeletal tension in the plane of the synapse through focal nucleation of actin via Wiskott–Aldrich syndrome protein (WASP), and contraction of the resultant actin filaments by myosin II. Following T‐cell activation, WASP is degraded, leading to cytoskeletal unraveling and tension decay, which result in synapse breaking. Thus, our study identifies and characterizes a mechanical program within otherwise highly motile T cells that sustains the symmetry and stability of the T cell–APC synaptic contact.

    更新日期:2020-01-02
  • Fetal monocytes possess increased metabolic capacity and replace primitive macrophages in tissue macrophage development
    EMBO J. (IF 11.227) Pub Date : 2020-01-02
    Fengqi Li; Katarzyna Maria Okreglicka; Lea Maria Pohlmeier; Christoph Schneider; Manfred Kopf

    Tissue‐resident macrophages (MΦTR) originate from at least two distinct waves of erythro‐myeloid progenitors (EMP) arising in the yolk sac (YS) at E7.5 and E8.5 with the latter going through a liver monocyte intermediate. The relative potential of these precursors in determining development and functional capacity of MΦTR remains unclear. Here, we studied development of alveolar macrophages (AM) after single and competitive transplantation of different precursors from YS, fetal liver, and fetal lung into neonatal Csf2ra−/− mice, which lack endogenous AM. Fetal monocytes, promoted by Myb, outcompeted primitive MΦ (pMΦ) in empty AM niches and preferentially developed to mature AM, which is associated with enhanced mitochondrial respiratory and glycolytic capacity and repression of the transcription factors c‐Maf and MafB. Interestingly, AM derived from pMΦ failed to efficiently clear alveolar proteinosis and protect from fatal lung failure following influenza virus infection. Thus, our data demonstrate superior developmental and functional capacity of fetal monocytes over pMΦ in AM development and underlying mechanisms explaining replacement of pMΦ in fetal tissues.

    更新日期:2020-01-02
  • Shugoshin 2—a new guardian for heat shock transcription
    EMBO J. (IF 11.227) Pub Date : 2019-12-30
    Amoldeep S Kainth; Rajyalakshmi Meduri; Vickky Pandit; Linda S Rubio; David S Gross

    Takii et al (2019) demonstrate in a recent issue of The EMBO Journal that the pericentromeric protein, SGO2, serves as a novel transcriptional coactivator of HSF1, contributing to PIC assembly and expression of Heat Shock Protein (HSP) genes. This finding highlights repurposing of a protein with a nuclear function to drive transcription of proteotoxic stress machinery genes.

    更新日期:2019-12-30
  • Towards the unified principles of transcription termination
    EMBO J. (IF 11.227) Pub Date : 2019-12-30
    Vladimir Svetlov; Evgeny Nudler

    Discovery of the role of bacterial RNase J1 in termination of transcription suggests common allosteric principles and mechanistic congruency of termination between bacteria and eukaryotes, in which an unrelated RNase Xrn2/Rat1 plays a similar role.

    更新日期:2019-12-30
  • Plant phosphate status drives host microbial preferences: a trade‐off between fungi and bacteria
    EMBO J. (IF 11.227) Pub Date : 2019-12-30
    Alga Zuccaro

    Recent discoveries show that plant recruitment of fungi and bacteria in a non‐mycorrhizal host follows different strategies dependent on phosphate availability. A new study by Morcillo et al (2019) demonstrates that volatile compounds synthesized by rhizobacteria contribute to phosphate starvation response‐dependent regulation of bacterial colonization and immune system activation in Arabidopsis thaliana plants.

    更新日期:2019-12-30
  • Absolute proteomic quantification reveals design principles of sperm flagellar chemosensation
    EMBO J. (IF 11.227) Pub Date : 2019-12-27
    Christian Trötschel; Hussein Hamzeh; Luis Alvarez; René Pascal; Fedir Lavryk; Wolfgang Bönigk; Heinz G Körschen; Astrid Müller; Ansgar Poetsch; Andreas Rennhack; Long Gui; Daniela Nicastro; Timo Strünker; Reinhard Seifert; U Benjamin Kaupp

    Cilia serve as cellular antennae that translate sensory information into physiological responses. In the sperm flagellum, a single chemoattractant molecule can trigger a Ca2+ rise that controls motility. The mechanisms underlying such ultra‐sensitivity are ill‐defined. Here, we determine by mass spectrometry the copy number of nineteen chemosensory signaling proteins in sperm flagella from the sea urchin Arbacia punctulata. Proteins are up to 1,000‐fold more abundant than the free cellular messengers cAMP, cGMP, H+, and Ca2+. Opto‐chemical techniques show that high protein concentrations kinetically compartmentalize the flagellum: Within milliseconds, cGMP is relayed from the receptor guanylate cyclase to a cGMP‐gated channel that serves as a perfect chemo‐electrical transducer. cGMP is rapidly hydrolyzed, possibly via “substrate channeling” from the channel to the phosphodiesterase PDE5. The channel/PDE5 tandem encodes cGMP turnover rates rather than concentrations. The rate‐detection mechanism allows continuous stimulus sampling over a wide dynamic range. The textbook notion of signal amplification—few enzyme molecules process many messenger molecules—does not hold for sperm flagella. Instead, high protein concentrations ascertain messenger detection. Similar mechanisms may occur in other small compartments like primary cilia or dendritic spines.

    更新日期:2019-12-27
  • NEDD4 and NEDD4L regulate Wnt signalling and intestinal stem cell priming by degrading LGR5 receptor
    EMBO J. (IF 11.227) Pub Date : 2019-12-23
    Laura Novellasdemunt; Anna Kucharska; Cara Jamieson; Maria Prange‐Barczynska; Anna Baulies; Pedro Antas; Jelte van der Vaart; Helmuth Gehart; Madelon M Maurice; Vivian SW Li

    The intestinal stem cell (ISC) marker LGR5 is a receptor for R‐spondin (RSPO) that functions to potentiate Wnt signalling in the proliferating crypt. It has been recently shown that Wnt plays a priming role for ISC self‐renewal by inducing RSPO receptor LGR5 expression. Despite its pivotal role in homeostasis, regeneration and cancer, little is known about the post‐translational regulation of LGR5. Here, we show that the HECT‐domain E3 ligases NEDD4 and NEDD4L are expressed in the crypt stem cell regions and regulate ISC priming by degrading LGR receptors. Loss of Nedd4 and Nedd4l enhances ISC proliferation, increases sensitivity to RSPO stimulation and accelerates tumour development in Apcmin mice with increased numbers of high‐grade adenomas. Mechanistically, we find that both NEDD4 and NEDD4L negatively regulate Wnt/β‐catenin signalling by targeting LGR5 receptor and DVL2 for proteasomal and lysosomal degradation. Our findings unveil the previously unreported post‐translational control of LGR receptors via NEDD4/NEDD4L to regulate ISC priming. Inactivation of NEDD4 and NEDD4L increases Wnt activation and ISC numbers, which subsequently enhances tumour predisposition and progression.

    更新日期:2019-12-23
  • Molecular mechanism of translational stalling by inhibitory codon combinations and poly(A) tracts
    EMBO J. (IF 11.227) Pub Date : 2019-12-20
    Petr Tesina; Laura N Lessen; Robert Buschauer; Jingdong Cheng; Colin Chih‐Chien Wu; Otto Berninghausen; Allen R Buskirk; Thomas Becker; Roland Beckmann; Rachel Green

    Inhibitory codon pairs and poly(A) tracts within the translated mRNA cause ribosome stalling and reduce protein output. The molecular mechanisms that drive these stalling events, however, are still unknown. Here, we use a combination of in vitro biochemistry, ribosome profiling, and cryo‐EM to define molecular mechanisms that lead to these ribosome stalls. First, we use an in vitro reconstituted yeast translation system to demonstrate that inhibitory codon pairs slow elongation rates which are partially rescued by increased tRNA concentration or by an artificial tRNA not dependent on wobble base‐pairing. Ribosome profiling data extend these observations by revealing that paused ribosomes with empty A sites are enriched on these sequences. Cryo‐EM structures of stalled ribosomes provide a structural explanation for the observed effects by showing decoding‐incompatible conformations of mRNA in the A sites of all studied stall‐ and collision‐inducing sequences. Interestingly, in the case of poly(A) tracts, the inhibitory conformation of the mRNA in the A site involves a nucleotide stacking array. Together, these data demonstrate a novel mRNA‐induced mechanisms of translational stalling in eukaryotic ribosomes.

    更新日期:2019-12-20
  • Mechanical coordination is sufficient to promote tissue replacement during metamorphosis in Drosophila
    EMBO J. (IF 11.227) Pub Date : 2019-12-20
    Carla Prat‐Rojo; Philippe‐Alexandre Pouille; Javier Buceta; Enrique Martin‐Blanco

    During development, cells coordinate to organize in coherent structures. Although it is now well established that physical forces are essential for implementing this coordination, the instructive roles of mechanical inputs are not clear. Here, we show that the replacement of the larval epithelia by the adult one in Drosophila demands the coordinated exchange of mechanical signals between two cell types, the histoblasts (adult precursors) organized in nests and the surrounding larval epidermal cells (LECs). An increasing stress gradient develops from the center of the nests toward the LECs as a result of the forces generated by histoblasts as they proliferate and by the LECs as they delaminate (push/pull coordination). This asymmetric radial coordination of expansive and contractile activities contributes to epithelial replacement. Our analyses support a model in which cell–cell mechanical communication is sufficient for the rearrangements that implement epithelial morphogenesis.

    更新日期:2019-12-20
  • Polo regulates Spindly to prevent premature stabilization of kinetochore‐microtubule attachments
    EMBO J. (IF 11.227) Pub Date : 2019-12-18
    João Barbosa; Torcato Martins; Tanja Bange; Li Tao; Carlos Conde; Claudio Sunkel

    Accurate chromosome segregation in mitosis requires sister kinetochores to bind to microtubules from opposite spindle poles. The stability of kinetochore–microtubule attachments is fine‐tuned to prevent or correct erroneous attachments while preserving amphitelic interactions. Polo kinase has been implicated in both stabilizing and destabilizing kinetochore–microtubule attachments. However, the mechanism underlying Polo–destabilizing activity remains elusive. Here, resorting to an RNAi screen in Drosophila for suppressors of a constitutively active Polo mutant, we identified a strong genetic interaction between Polo and the Rod–ZW10–Zwilch (RZZ) complex, whose kinetochore accumulation has been shown to antagonize microtubule stability. We find that Polo phosphorylates Spindly and impairs its ability to bind to Zwilch. This precludes dynein‐mediated removal of the RZZ from kinetochores and consequently delays the formation of stable end‐on attachments. We propose that high Polo‐kinase activity following mitotic entry directs the RZZ complex to minimize premature stabilization of erroneous attachments, whereas a decrease in active Polo in later mitotic stages allows the formation of stable amphitelic spindle attachments. Our findings demonstrate that Polo tightly regulates the RZZ–Spindly–dynein module during mitosis to ensure the fidelity of chromosome segregation.

    更新日期:2019-12-19
  • A destabilised metabolic niche provokes loss of a subpopulation of aged muscle stem cells
    EMBO J. (IF 11.227) Pub Date : 2019-12-04
    Brendan Evano; Shahragim Tajbakhsh

    Ageing is a multi‐factorial condition that results in a gradual decline in tissue and organ function. Systemic, local and intrinsic factors play major roles in this process that also results in a decline in stem cell number and function. In this issue of The EMBO Journal, Li et al (2019) show that a subpopulation of mouse muscle stem cells is depleted in aged mice through loss of niche‐derived granulocyte colony‐stimulating factor (G‐CSF).

    更新日期:2019-12-17
  • The pericentromeric protein shugoshin 2 cooperates with HSF1 in heat shock response and RNA Pol II recruitment
    EMBO J. (IF 11.227) Pub Date : 2019-10-28
    Ryosuke Takii; Mitsuaki Fujimoto; Masaki Matsumoto; Pratibha Srivastava; Arpit Katiyar; Keiich I Nakayama; Akira Nakai
    更新日期:2019-12-17
  • Muscle‐secreted granulocyte colony‐stimulating factor functions as metabolic niche factor ameliorating loss of muscle stem cells in aged mice
    EMBO J. (IF 11.227) Pub Date : 2019-11-18
    Hu Li; Qian Chen; Changyin Li; Ran Zhong; Yixia Zhao; Qianying Zhang; Weimin Tong; Dahai Zhu; Yong Zhang
    更新日期:2019-12-17
  • LIN28A loss of function is associated with Parkinson's disease pathogenesis
    EMBO J. (IF 11.227) Pub Date : 2019-11-21
    Mi‐Yoon Chang; Boram Oh; Jang‐Eun Choi; Yanuar Alan Sulistio; Hye‐Ji Woo; Ayoung Jo; Jinil Kim; Eun‐Hee Kim; Seung Won Kim; Jungwook Hwang; Jungyun Park; Jae‐Jin Song; Oh‐Chan Kwon; Hyongbum Henry Kim; Young‐Hoon Kim; Joo Yeon Ko; Jun Young Heo; Min Joung Lee; Moses Lee; Murim Choi; Sun Ju Chung; Hyun‐Seob Lee; Sang‐Hun Lee
    更新日期:2019-12-17
  • Pathogen‐induced pH changes regulate the growth‐defense balance in plants
    EMBO J. (IF 11.227) Pub Date : 2019-11-18
    Christopher Kesten; Francisco M Gámez‐Arjona; Alexandra Menna; Stefan Scholl; Susanne Dora; Apolonio Ignacio Huerta; Hsin‐Yao Huang; Nico Tintor; Toshinori Kinoshita; Martijn Rep; Melanie Krebs; Karin Schumacher; Clara Sánchez‐Rodríguez
    更新日期:2019-12-17
  • Stress signaling and cellular proliferation reverse the effects of mitochondrial mistranslation
    EMBO J. (IF 11.227) Pub Date : 2019-11-13
    Nicola Ferreira; Kara L Perks; Giulia Rossetti; Danielle L Rudler; Laetitia A Hughes; Judith A Ermer; Louis H Scott; Irina Kuznetsova; Tara R Richman; Vinod K Narayana; Laila N Abudulai; Anne‐Marie J Shearwood; Henrietta Cserne Szappanos; Dedreia Tull; George C Yeoh; Livia C Hool; Aleksandra Filipovska; Oliver Rackham
    更新日期:2019-12-17
  • Break‐induced replication plays a prominent role in long‐range repeat‐mediated deletion
    EMBO J. (IF 11.227) Pub Date : 2019-10-01
    Qing Hu; Hongyan Lu; Hongjun Wang; Shibo Li; Lan Truong; Jun Li; Shuo Liu; Rong Xiang; Xiaohua Wu
    更新日期:2019-12-17
  • Phosphoproteomics reveals conserved exercise‐stimulated signaling and AMPK regulation of store‐operated calcium entry
    EMBO J. (IF 11.227) Pub Date : 2019-08-05
    Marin E Nelson; Benjamin L Parker; James G Burchfield; Nolan J Hoffman; Elise J Needham; Kristen C Cooke; Timur Naim; Lykke Sylow; Naomi XY Ling; Deanne Francis; Dougall M Norris; Rima Chaudhuri; Jonathan S Oakhill; Erik A Richter; Gordon S Lynch; Jacqueline Stöckli; David E James
    更新日期:2019-12-17
  • The torpedo effect in Bacillus subtilis: RNase J1 resolves stalled transcription complexes
    EMBO J. (IF 11.227) Pub Date : 2019-12-16
    Michaela Šiková; Jana Wiedermannová; Martin Převorovský; Ivan Barvík; Petra Sudzinová; Olga Kofroňová; Oldřich Benada; Hana Šanderová; Ciarán Condon; Libor Krásný

    RNase J1 is the major 5′‐to‐3′ bacterial exoribonuclease. We demonstrate that in its absence, RNA polymerases (RNAPs) are redistributed on DNA, with increased RNAP occupancy on some genes without a parallel increase in transcriptional output. This suggests that some of these RNAPs represent stalled, non‐transcribing complexes. We show that RNase J1 is able to resolve these stalled RNAP complexes by a “torpedo” mechanism, whereby RNase J1 degrades the nascent RNA and causes the transcription complex to disassemble upon collision with RNAP. A heterologous enzyme, yeast Xrn1 (5′‐to‐3′ exonuclease), is less efficient than RNase J1 in resolving stalled Bacillus subtilis RNAP, suggesting that the effect is RNase‐specific. Our results thus reveal a novel general principle, whereby an RNase can participate in genome‐wide surveillance of stalled RNAP complexes, preventing potentially deleterious transcription–replication collisions.

    更新日期:2019-12-17
  • Molecular and physiological consequences of faulty eukaryotic ribonucleotide excision repair
    EMBO J. (IF 11.227) Pub Date : 2019-12-12
    Vanessa Kellner; Brian Luke

    The duplication of the eukaryotic genome is an intricate process that has to be tightly safe‐guarded. One of the most frequently occurring errors during DNA synthesis is the mis‐insertion of a ribonucleotide instead of a deoxyribonucleotide. Ribonucleotide excision repair (RER) is initiated by RNase H2 and results in error‐free removal of such mis‐incorporated ribonucleotides. If left unrepaired, DNA‐embedded ribonucleotides result in a variety of alterations within chromosomal DNA, which ultimately lead to genome instability. Here, we review how genomic ribonucleotides lead to chromosomal aberrations and discuss how the tight regulation of RER timing may be important for preventing unwanted DNA damage. We describe the structural impact of unrepaired ribonucleotides on DNA and chromatin and comment on the potential consequences for cellular fitness. In the context of the molecular mechanisms associated with faulty RER, we have placed an emphasis on how and why increased levels of genomic ribonucleotides are associated with severe autoimmune syndromes, neuropathology, and cancer. In addition, we discuss therapeutic directions that could be followed for pathologies associated with defective removal of ribonucleotides from double‐stranded DNA.

    更新日期:2019-12-13
  • Biomechanical stress regulates mammalian tooth replacement via the integrin β1‐RUNX2‐Wnt pathway
    EMBO J. (IF 11.227) Pub Date : 2019-12-12
    Xiaoshan Wu; Jinrong Hu; Guoqing Li; Yan Li; Yang Li; Jing Zhang; Fu Wang; Ang Li; Lei Hu; Zhipeng Fan; Shouqin Lü; Gang Ding; Chunmei Zhang; Jinsong Wang; Mian Long; Songlin Wang

    Renewal of integumentary organs occurs cyclically throughout an organism's lifetime, but the mechanism that initiates each cycle remains largely unknown. In a miniature pig model of tooth development that resembles tooth development in humans, the permanent tooth did not begin transitioning from the resting to the initiation stage until the deciduous tooth began to erupt. This eruption released the accumulated mechanical stress inside the mandible. Mechanical stress prevented permanent tooth development by regulating expression and activity of the integrin β1‐ERK1‐RUNX2 axis in the surrounding mesenchyme. We observed similar molecular expression patterns in human tooth germs. Importantly, the release of biomechanical stress induced downregulation of RUNX2‐wingless/integrated (Wnt) signaling in the mesenchyme between the deciduous and permanent tooth and upregulation of Wnt signaling in the epithelium of the permanent tooth, triggering initiation of its development. Consequently, our findings identified biomechanical stress‐associated Wnt modulation as a critical initiator of organ renewal, possibly shedding light on the mechanisms of integumentary organ regeneration.

    更新日期:2019-12-13
  • Legionella pneumophila regulates the activity of UBE2N by deamidase‐mediated deubiquitination
    EMBO J. (IF 11.227) Pub Date : 2019-12-11
    Ninghai Gan; Hongxin Guan; Yini Huang; Ting Yu; Jiaqi Fu; Ernesto S Nakayasu; Kedar Puvar; Chittaranjan Das; Dongmei Wang; Songying Ouyang; Zhao‐Qing Luo

    The Legionella pneumophila effector MavC induces ubiquitination of the E2 ubiquitin‐conjugating enzyme UBE2N by transglutamination, thereby abolishing its function in the synthesis of K63‐type polyubiquitin chains. The inhibition of UBE2N activity creates a conundrum because this E2 enzyme is important in multiple signaling pathways, including some that are important for intracellular L. pneumophila replication. Here, we show that prolonged inhibition of UBE2N activity by MavC restricts intracellular bacterial replication and that the activity of UBE2N is restored by MvcA, an ortholog of MavC (50% identity) with ubiquitin deamidase activity. MvcA functions to deubiquitinate UBE2N‐Ub using the same catalytic triad required for its deamidase activity. Structural analysis of the MvcA‐UBE2N‐Ub complex reveals a crucial role of the insertion domain in MvcA in substrate recognition. Our study establishes a deubiquitination mechanism catalyzed by a deamidase, which, together with MavC, imposes temporal regulation of the activity of UBE2N during L. pneumophila infection.

    更新日期:2019-12-11
  • LRRK2 regulates endoplasmic reticulum–mitochondrial tethering through the PERK‐mediated ubiquitination pathway
    EMBO J. (IF 11.227) Pub Date : 2019-12-10
    Toshihiko Toyofuku; Yuki Okamoto; Takako Ishikawa; Shigemi Sasawatari; Atsushi Kumanogoh

    Mutations in the leucine‐rich repeat kinase 2 (LRRK2) gene are the most common cause of familial Parkinson's disease (PD). Impaired mitochondrial function is suspected to play a major role in PD. Nonetheless, the underlying mechanism by which impaired LRRK2 activity contributes to PD pathology remains unclear. Here, we identified the role of LRRK2 in endoplasmic reticulum (ER)–mitochondrial tethering, which is essential for mitochondrial bioenergetics. LRRK2 regulated the activities of E3 ubiquitin ligases MARCH5, MULAN, and Parkin via kinase‐dependent protein–protein interactions. Kinase‐active LRRK2(G2019S) dissociated from these ligases, leading to their PERK‐mediated phosphorylation and activation, thereby increasing ubiquitin‐mediated degradation of ER–mitochondrial tethering proteins. By contrast, kinase‐dead LRRK2(D1994A)‐bound ligases blocked PERK‐mediated phosphorylation and activation of E3 ligases, thereby increasing the levels of ER–mitochondrial tethering proteins. Thus, the role of LRRK2 in the ER–mitochondrial interaction represents an important control point for cell fate and pathogenesis in PD.

    更新日期:2019-12-11
  • The GTPase Rab39a promotes phagosome maturation into MHC‐I antigen‐presenting compartments
    EMBO J. (IF 11.227) Pub Date : 2019-12-10
    Freidrich M Cruz; Jeff D Colbert; Kenneth L Rock

    For CD8 T lymphocytes to mount responses to cancer and virally‐infected cells, dendritic cells must capture antigens present in tissues and display them as peptides bound to MHC‐I molecules. This is most often accomplished through a pathway called antigen cross‐presentation (XPT). Here, we report that the vesicular trafficking protein Rab39a is needed for optimal cross‐presentation by dendritic cells in vitro and cross‐priming of CD8 T cells in vivo. Without Rab39a, MHC‐I presentation of intraphagosomal peptides is inhibited, indicating that Rab39a converts phagosomes into peptide‐loading compartments. In this process, Rab39a promotes the delivery of MHC‐I molecules from the endoplasmic reticulum (ER) to phagosomes, and increases the levels of peptide‐empty MHC‐I conformers that can be loaded with peptide in this compartment. Rab39a also increases the levels of Sec22b and NOX2, previously recognized to participate in cross‐presentation, on phagosomes, thereby filling in a missing link into how phagosomes mature into cross‐presenting vesicles.

    更新日期:2019-12-11
  • ESCRT machinery mediates selective microautophagy of endoplasmic reticulum in yeast
    EMBO J. (IF 11.227) Pub Date : 2019-12-05
    Jasmin A Schäfer; Julia P Schessner; Peter W Bircham; Takuma Tsuji; Charlotta Funaya; Oliver Pajonk; Katharina Schaeff; Giulia Ruffini; Dimitrios Papagiannidis; Michael Knop; Toyoshi Fujimoto; Sebastian Schuck

    ER‐phagy, the selective autophagy of endoplasmic reticulum (ER), safeguards organelle homeostasis by eliminating misfolded proteins and regulating ER size. ER‐phagy can occur by macroautophagic and microautophagic mechanisms. While dedicated machinery for macro‐ER‐phagy has been discovered, the molecules and mechanisms mediating micro‐ER‐phagy remain unknown. Here, we first show that micro‐ER‐phagy in yeast involves the conversion of stacked cisternal ER into multilamellar ER whorls during microautophagic uptake into lysosomes. Second, we identify the conserved Nem1‐Spo7 phosphatase complex and the ESCRT machinery as key components for micro‐ER‐phagy. Third, we demonstrate that macro‐ and micro‐ER‐phagy are parallel pathways with distinct molecular requirements. Finally, we provide evidence that the ESCRT machinery directly functions in scission of the lysosomal membrane to complete the microautophagic uptake of ER. These findings establish a framework for a mechanistic understanding of micro‐ER‐phagy and, thus, a comprehensive appreciation of the role of autophagy in ER homeostasis.

    更新日期:2019-12-05
  • Rhizobacterium‐derived diacetyl modulates plant immunity in a phosphate‐dependent manner
    EMBO J. (IF 11.227) Pub Date : 2019-12-05
    Rafael JL Morcillo; Sunil K Singh; Danxia He; Guo An; Juan I Vílchez; Kai Tang; Fengtong Yuan; Yazhou Sun; Chuyang Shao; Song Zhang; Yu Yang; Xiaomin Liu; Yashan Dang; Wei Wang; Jinghui Gao; Weichang Huang; Mingguang Lei; Chun‐Peng Song; Jian‐Kang Zhu; Alberto P Macho; Pual W Paré; Huiming Zhang

    Plants establish mutualistic associations with beneficial microbes while deploying the immune system to defend against pathogenic ones. Little is known about the interplay between mutualism and immunity and the mediator molecules enabling such crosstalk. Here, we show that plants respond differentially to a volatile bacterial compound through integral modulation of the immune system and the phosphate‐starvation response (PSR) system, resulting in either mutualism or immunity. We found that exposure of Arabidopsis thaliana to a known plant growth‐promoting rhizobacterium can unexpectedly have either beneficial or deleterious effects to plants. The beneficial‐to‐deleterious transition is dependent on availability of phosphate to the plants and is mediated by diacetyl, a bacterial volatile compound. Under phosphate‐sufficient conditions, diacetyl partially suppresses plant production of reactive oxygen species (ROS) and enhances symbiont colonization without compromising disease resistance. Under phosphate‐deficient conditions, diacetyl enhances phytohormone‐mediated immunity and consequently causes plant hyper‐sensitivity to phosphate deficiency. Therefore, diacetyl affects the type of relation between plant hosts and certain rhizobacteria in a way that depends on the plant's phosphate‐starvation response system and phytohormone‐mediated immunity.

    更新日期:2019-12-05
  • PTPN2 phosphatase deletion in T cells promotes anti‐tumour immunity and CAR T‐cell efficacy in solid tumours
    EMBO J. (IF 11.227) Pub Date : 2019-12-05
    Florian Wiede; Kun‐Hui Lu; Xin Du; Shuwei Liang; Katharina Hochheiser; Garron T Dodd; Pei K Goh; Conor Kearney; Deborah Meyran; Paul A Beavis; Melissa A Henderson; Simone L Park; Jason Waithman; Sheng Zhang; Zhong‐Yin Zhang; Jane Oliaro; Thomas Gebhardt; Phillip K Darcy; Tony Tiganis

    Although adoptive T‐cell therapy has shown remarkable clinical efficacy in haematological malignancies, its success in combating solid tumours has been limited. Here, we report that PTPN2 deletion in T cells enhances cancer immunosurveillance and the efficacy of adoptively transferred tumour‐specific T cells. T‐cell‐specific PTPN2 deficiency prevented tumours forming in aged mice heterozygous for the tumour suppressor p53. Adoptive transfer of PTPN2‐deficient CD8+ T cells markedly repressed tumour formation in mice bearing mammary tumours. Moreover, PTPN2 deletion in T cells expressing a chimeric antigen receptor (CAR) specific for the oncoprotein HER‐2 increased the activation of the Src family kinase LCK and cytokine‐induced STAT‐5 signalling, thereby enhancing both CAR T‐cell activation and homing to CXCL9/10‐expressing tumours to eradicate HER‐2+ mammary tumours in vivo. Our findings define PTPN2 as a target for bolstering T‐cell‐mediated anti‐tumour immunity and CAR T‐cell therapy against solid tumours.

    更新日期:2019-12-05
  • Lignin‐based barrier restricts pathogens to the infection site and confers resistance in plants
    EMBO J. (IF 11.227) Pub Date : 2019-09-26
    Myoung‐Hoon Lee; Hwi Seong Jeon; Seu Ha Kim; Joo Hee Chung; Daniele Roppolo; Hye‐Jung Lee; Hong Joo Cho; Yuki Tobimatsu; John Ralph; Ohkmae K Park
    更新日期:2019-12-03
  • Beyond inflammasomes: emerging function of gasdermins during apoptosis and NETosis
    EMBO J. (IF 11.227) Pub Date : 2019-12-03
    Kaiwen W Chen; Benjamin Demarco; Petr Broz

    Programmed cell death is a key mechanism involved in several biological processes ranging from development and homeostasis to immunity, where it promotes the removal of stressed, damaged, malignant or infected cells. Abnormalities in the pathways leading to initiation of cell death or removal of dead cells are consequently associated with a range of human diseases including infections, autoinflammatory disease, neurodegenerative disease and cancer. Apoptosis, pyroptosis and NETosis are three well‐studied modes of cell death that were traditionally believed to be independent of one another, but emerging evidence indicates that there is extensive cross‐talk between them, and that all three pathways can converge onto the activation of the same cell death effector—the pore‐forming protein Gasdermin D (GSDMD). In this review, we highlight recent advances in gasdermin research, with a particular focus on the role of gasdermins in pyroptosis, NETosis and apoptosis, as well as cell type‐specific consequences of gasdermin activation. In addition, we discuss controversies surrounding a related gasdermin family protein, Gasdermin E (GSDME), in mediating pyroptosis and secondary necrosis following apoptosis, chemotherapy and inflammasome activation.

    更新日期:2019-12-03
  • Peer Review beyond Journals
    EMBO J. (IF 11.227) Pub Date : 2019-12-02
    Bernd Pulverer; Thomas Lemberger

    The EMBO Journal has extended its Transparent Process beyond journal confines to post referee comments alongside preprint versions of papers and to partner with Review Commons, a pre‐journal peer‐review platform for Refereed Preprints in the life sciences.

    更新日期:2019-12-02
  • More or less – the same? mRNA fluctuations are balanced during translation
    EMBO J. (IF 11.227) Pub Date : 2019-10-22
    Itamar Kozlovski; Reuven Agami

    Transcription factors have been traditionally studied at the level of transcription, neglecting a potential impact on protein translation. A new study published by Lorent et al (2019) describes a mechanism by which fluctuations in mRNA abundance are counteracted during translation upon estrogen receptor‐alpha (ERα) depletion. This phenomenon, termed translational offsetting, is prevalent and programmed to maintain essential proteins at constant levels.

    更新日期:2019-12-02
  • Translational offsetting as a mode of estrogen receptor α‐dependent regulation of gene expression
    EMBO J. (IF 11.227) Pub Date : 2019-09-26
    Julie Lorent; Eric P Kusnadi; Vincent van Hoef; Richard J Rebello; Matthew Leibovitch; Johannes Ristau; Shan Chen; Mitchell G Lawrence; Krzysztof J Szkop; Baila Samreen; Preetika Balanathan; Francesca Rapino; Pierre Close; Patricia Bukczynska; Karin Scharmann; Itsuhiro Takizawa; Gail P Risbridger; Luke A Selth; Sebastian A Leidel; Qishan Lin; Ivan Topisirovic; Ola Larsson; Luc Furic
    更新日期:2019-12-02
  • Tau deletion reduces plaque‐associated BACE1 accumulation and decelerates plaque formation in a mouse model of Alzheimer's disease
    EMBO J. (IF 11.227) Pub Date : 2019-11-07
    Finn Peters; Hazal Salihoglu; Katrin Pratsch; Etienne Herzog; Martina Pigoni; Carmelo Sgobio; Stefan F Lichtenthaler; Ulf Neumann; Jochen Herms
    更新日期:2019-12-02
  • Senescent human melanocytes drive skin ageing via paracrine telomere dysfunction
    EMBO J. (IF 11.227) Pub Date : 2019-10-21
    Stella Victorelli; Anthony Lagnado; Jessica Halim; Will Moore; Duncan Talbot; Karen Barrett; James Chapman; Jodie Birch; Mikolaj Ogrodnik; Alexander Meves; Jeff S Pawlikowski; Diana Jurk; Peter D Adams; Diana van Heemst; Marian Beekman; P Eline Slagboom; David A Gunn; João F Passos
    更新日期:2019-12-02
  • The Wnt/Ca2+ pathway is involved in interneuronal communication mediated by tunneling nanotubes
    EMBO J. (IF 11.227) Pub Date : 2019-10-18
    Jessica Y Vargas; Frida Loria; Yuan‐Ju Wu; Gonzalo Córdova; Takashi Nonaka; Sebastien Bellow; Sylvie Syan; Masato Hasegawa; Geeske M van Woerden; Capucine Trollet; Chiara Zurzolo
    更新日期:2019-12-02
  • Cul3‐Klhl18 ubiquitin ligase modulates rod transducin translocation during light‐dark adaptation
    EMBO J. (IF 11.227) Pub Date : 2019-11-07
    Taro Chaya; Ryotaro Tsutsumi; Leah Rie Varner; Yamato Maeda; Satoyo Yoshida; Takahisa Furukawa
    更新日期:2019-12-02
  • NuMA assemblies organize microtubule asters to establish spindle bipolarity in acentrosomal human cells
    EMBO J. (IF 11.227) Pub Date : 2019-11-29
    Takumi Chinen; Shohei Yamamoto; Yutaka Takeda; Koki Watanabe; Kanako Kuroki; Kaho Hashimoto; Daisuke Takao; Daiju Kitagawa
    更新日期:2019-11-30
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