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Journal Cover Cell
  [SJR: 28.188]   [H-I: 616]   [910 followers]  Follow
    
   Full-text available via subscription Subscription journal
   ISSN (Print) 0092-8674 - ISSN (Online) 1097-4172
   Published by Elsevier Homepage  [3123 journals]
  • Pamela Sklar (1959–2017)
    • Abstract: Publication date: 14 December 2017
      Source:Cell, Volume 171, Issue 7
      Author(s): Eric J. Nestler


      PubDate: 2018-02-15T15:59:20Z
       
  • CD19 CAR T Cells
    • Abstract: Publication date: 14 December 2017
      Source:Cell, Volume 171, Issue 7
      Author(s): Michel Sadelain
      CARs are synthetic receptors that reprogram immune cells for therapeutic purposes. They comprise three canonical domains for antigen recognition, T cell activation, and costimulation. The CAR cDNA is genetically integrated in the T cell genome. Autologous CAR T cells are generated from the patient’s peripheral blood T cells and expand in the recipient to eliminate the targeted tumor. To view this Bench to Bedside, open or download the PDF.
      Teaser CARs are synthetic receptors that reprogram immune cells for therapeutic purposes. They comprise three canonical domains for antigen recognition, T cell activation, and costimulation. The CAR cDNA is genetically integrated in the T cell genome. Autologous CAR T cells are generated from the patient’s peripheral blood T cells and expand in the recipient to eliminate the targeted tumor. To view this Bench to Bedside, open or download the PDF.

      PubDate: 2018-02-15T15:59:20Z
       
  • Big Role for a Tiny Genome
    • Abstract: Publication date: 14 December 2017
      Source:Cell, Volume 171, Issue 7
      Author(s): Angela E. Douglas
      In this issue of Cell, Salem et al. demonstrate a remarkable instance of herbivory dependent on a co-evolved mutualism with specialized bacteria. Despite having a tiny genome and limited metabolic repertoire, the bacteria in Cassida beetles produce pectinases predicted to mediate degradation of plant cell walls in the insect diet.
      Teaser In this issue of Cell, Salem et al. demonstrate a remarkable instance of herbivory dependent on a co-evolved mutualism with specialized bacteria. Despite having a tiny genome and limited metabolic repertoire, the bacteria in Cassida beetles produce pectinases predicted to mediate degradation of plant cell walls in the insect diet.

      PubDate: 2018-02-15T15:59:20Z
       
  • Less Lipid, More Commitment
    • Abstract: Publication date: 14 December 2017
      Source:Cell, Volume 171, Issue 7
      Author(s): Manuel Llinás
      Sexual differentiation of the malaria parasite is a pre-requisite for transmission from humans to the mosquito vector and has emerged as a target for intervention in eradication efforts. In this issue of Cell, a study from Marti, Clardy, and colleagues (Brancucci et al., 2017) describes a host-derived lipid lysophosphatidylcholine (LysoPC) that regulates sexual commitment.
      Teaser Sexual differentiation of the malaria parasite is a pre-requisite for transmission from humans to the mosquito vector and has emerged as a target for intervention in eradication efforts. In this issue of Cell, a study from Marti, Clardy, and colleagues (Brancucci et al., 2017) describes a host-derived lipid lysophosphatidylcholine (LysoPC) that regulates sexual commitment.

      PubDate: 2018-02-15T15:59:20Z
       
  • On the Design of Combination Cancer Therapy
    • Abstract: Publication date: 14 December 2017
      Source:Cell, Volume 171, Issue 7
      Author(s): James H. Doroshow, Richard M. Simon
      Combination therapy programs are the hallmark of the successful treatment of all forms of human malignancies. In this issue of Cell, Palmer and Sorger present data suggesting that cell culture results indicative of synergistic anticancer drug interactions rarely translate clinically and that the results of combination therapies in mouse models or human clinical trials, even if successful, are best explained by the independent activities of the individually administered drugs.
      Teaser Combination therapy programs are the hallmark of the successful treatment of all forms of human malignancies. In this issue of Cell, Palmer and Sorger present data suggesting that cell culture results indicative of synergistic anticancer drug interactions rarely translate clinically and that the results of combination therapies in mouse models or human clinical trials, even if successful, are best explained by the independent activities of the individually administered drugs.

      PubDate: 2018-02-15T15:59:20Z
       
  • FIX It in One Go: Enhanced Factor IX Gene Therapy for Hemophilia B
    • Abstract: Publication date: 14 December 2017
      Source:Cell, Volume 171, Issue 7
      Author(s): David Lillicrap
      A phase 1/2 clinical trial of AAV-mediated gene therapy in patients with hemophilia B using an enhanced specific activity factor IX (FIX) transgene reports sustained levels of FIX levels, leading to the near elimination of bleeding for more than a year and without serious adverse side effects. These results are the best outcome to date for hemophilia gene therapy.
      Teaser A phase 1/2 clinical trial of AAV-mediated gene therapy in patients with hemophilia B using an enhanced specific activity factor IX (FIX) transgene reports sustained levels of FIX levels, leading to the near elimination of bleeding for more than a year and without serious adverse side effects. These results are the best outcome to date for hemophilia gene therapy.

      PubDate: 2018-02-15T15:59:20Z
       
  • Our Gut Microbiome: The Evolving Inner Self
    • Abstract: Publication date: 14 December 2017
      Source:Cell, Volume 171, Issue 7
      Author(s): Parag Kundu, Eran Blacher, Eran Elinav, Sven Pettersson
      The “holobiont” concept, defined as the collective contribution of the eukaryotic and prokaryotic counterparts to the multicellular organism, introduces a complex definition of individuality enabling a new comprehensive view of human evolution and personalized characteristics. Here, we provide snapshots of the evolving microbial-host associations and relations during distinct milestones across the lifespan of a human being. We discuss the current knowledge of biological symbiosis between the microbiome and its host and portray the challenges in understanding these interactions and their potential effects on human physiology, including microbiome-nervous system inter-relationship and its relevance to human variation and individuality.
      Teaser Host-microbe associations vary and evolve during the lifespans of human beings. This review provides insights into symbiotic relationships between the microbiome and its human host in the context of physiology and aging.

      PubDate: 2018-02-15T15:59:20Z
       
  • In Vivo Target Gene Activation via CRISPR/Cas9-Mediated
           Trans-epigenetic Modulation
    • Abstract: Publication date: 14 December 2017
      Source:Cell, Volume 171, Issue 7
      Author(s): Hsin-Kai Liao, Fumiyuki Hatanaka, Toshikazu Araoka, Pradeep Reddy, Min-Zu Wu, Yinghui Sui, Takayoshi Yamauchi, Masahiro Sakurai, David D. O’Keefe, Estrella Núñez-Delicado, Pedro Guillen, Josep M. Campistol, Cheng-Jang Wu, Li-Fan Lu, Concepcion Rodriguez Esteban, Juan Carlos Izpisua Belmonte
      Current genome-editing systems generally rely on inducing DNA double-strand breaks (DSBs). This may limit their utility in clinical therapies, as unwanted mutations caused by DSBs can have deleterious effects. CRISPR/Cas9 system has recently been repurposed to enable target gene activation, allowing regulation of endogenous gene expression without creating DSBs. However, in vivo implementation of this gain-of-function system has proven difficult. Here, we report a robust system for in vivo activation of endogenous target genes through trans-epigenetic remodeling. The system relies on recruitment of Cas9 and transcriptional activation complexes to target loci by modified single guide RNAs. As proof-of-concept, we used this technology to treat mouse models of diabetes, muscular dystrophy, and acute kidney disease. Results demonstrate that CRISPR/Cas9-mediated target gene activation can be achieved in vivo, leading to measurable phenotypes and amelioration of disease symptoms. This establishes new avenues for developing targeted epigenetic therapies against human diseases. Video
      Graphical abstract image Teaser In vivo delivery of a Cas9-based epigenetic gene activation system ameliorates disease phenotypes in mouse models of type I diabetes, acute kidney injury, and muscular dystrophy

      PubDate: 2018-02-15T15:59:20Z
       
  • Resetting the Yeast Epigenome with Human Nucleosomes
    • Abstract: Publication date: 14 December 2017
      Source:Cell, Volume 171, Issue 7
      Author(s): David M. Truong, Jef D. Boeke
      Humans and yeast are separated by a billion years of evolution, yet their conserved histones retain central roles in gene regulation. Here, we “reset” yeast to use core human nucleosomes in lieu of their own (a rare event taking 20 days), which initially only worked with variant H3.1. The cells adapt by acquiring suppressor mutations in cell-division genes or by acquiring certain aneuploid states. Converting five histone residues to their yeast counterparts restored robust growth. We reveal that humanized nucleosomes are positioned according to endogenous yeast DNA sequence and chromatin-remodeling network, as judged by a yeast-like nucleosome repeat length. However, human nucleosomes have higher DNA occupancy, globally reduce RNA content, and slow adaptation to new conditions by delaying chromatin remodeling. These humanized yeasts (including H3.3) pose fundamental new questions about how chromatin is linked to many cell processes and provide a platform to study histone variants via yeast epigenome reprogramming.
      Graphical abstract image Teaser Yeast can survive with human histones, providing insight into the regulation of nucleosome positioning and remodeling.

      PubDate: 2018-02-15T15:59:20Z
       
  • Drastic Genome Reduction in an Herbivore’s Pectinolytic Symbiont
    • Abstract: Publication date: 14 December 2017
      Source:Cell, Volume 171, Issue 7
      Author(s): Hassan Salem, Eugen Bauer, Roy Kirsch, Aileen Berasategui, Michael Cripps, Benjamin Weiss, Ryuichi Koga, Kayoko Fukumori, Heiko Vogel, Takema Fukatsu, Martin Kaltenpoth
      Pectin, an integral component of the plant cell wall, is a recalcitrant substrate against enzymatic challenges by most animals. In characterizing the source of a leaf beetle’s (Cassida rubiginosa) pectin-degrading phenotype, we demonstrate its dependency on an extracellular bacterium housed in specialized organs connected to the foregut. Despite possessing the smallest genome (0.27 Mb) of any organism not subsisting within a host cell, the symbiont nonetheless retained a functional pectinolytic metabolism targeting the polysaccharide’s two most abundant classes: homogalacturonan and rhamnogalacturonan I. Comparative transcriptomics revealed pectinase expression to be enriched in the symbiotic organs, consistent with enzymatic buildup in these structures following immunostaining with pectinase-targeting antibodies. Symbiont elimination results in a drastically reduced host survivorship and a diminished capacity to degrade pectin. Collectively, our findings highlight symbiosis as a strategy for an herbivore to metabolize one of nature’s most complex polysaccharides and a universal component of plant tissues.
      Graphical abstract image Teaser A proteobacterial symbiont with the smallest known genome of an extracellular bacterium provides its host beetle with key enzymes to break down pectin in plant-based food, giving a striking example of symbiosis and evolutionary adaptation.

      PubDate: 2018-02-15T15:59:20Z
       
  • Lysophosphatidylcholine Regulates Sexual Stage Differentiation in the
           Human Malaria Parasite Plasmodium falciparum
    • Abstract: Publication date: 14 December 2017
      Source:Cell, Volume 171, Issue 7
      Author(s): Nicolas M.B. Brancucci, Joseph P. Gerdt, ChengQi Wang, Mariana De Niz, Nisha Philip, Swamy R. Adapa, Min Zhang, Eva Hitz, Igor Niederwieser, Sylwia D. Boltryk, Marie-Claude Laffitte, Martha A. Clark, Christof Grüring, Deepali Ravel, Alexandra Blancke Soares, Allison Demas, Selina Bopp, Belén Rubio-Ruiz, Ana Conejo-Garcia, Dyann F. Wirth, Edyta Gendaszewska-Darmach, Manoj T. Duraisingh, John H. Adams, Till S. Voss, Andrew P. Waters, Rays H.Y. Jiang, Jon Clardy, Matthias Marti
      Transmission represents a population bottleneck in the Plasmodium life cycle and a key intervention target of ongoing efforts to eradicate malaria. Sexual differentiation is essential for this process, as only sexual parasites, called gametocytes, are infective to the mosquito vector. Gametocyte production rates vary depending on environmental conditions, but external stimuli remain obscure. Here, we show that the host-derived lipid lysophosphatidylcholine (LysoPC) controls P. falciparum cell fate by repressing parasite sexual differentiation. We demonstrate that exogenous LysoPC drives biosynthesis of the essential membrane component phosphatidylcholine. LysoPC restriction induces a compensatory response, linking parasite metabolism to the activation of sexual-stage-specific transcription and gametocyte formation. Our results reveal that malaria parasites can sense and process host-derived physiological signals to regulate differentiation. These data close a critical knowledge gap in parasite biology and introduce a major component of the sexual differentiation pathway in Plasmodium that may provide new approaches for blocking malaria transmission.
      Graphical abstract image Teaser The host-derived lipid lysophosphatidylcholine controls Plasmodium falciparum cell fate by repressing parasite sexual differentiation, a key step in malaria transmission.

      PubDate: 2018-02-15T15:59:20Z
       
  • Post-transcriptional Regulation of De Novo Lipogenesis by
           mTORC1-S6K1-SRPK2 Signaling
    • Abstract: Publication date: 14 December 2017
      Source:Cell, Volume 171, Issue 7
      Author(s): Gina Lee, Yuxiang Zheng, Sungyun Cho, Cholsoon Jang, Christina England, Jamie M. Dempsey, Yonghao Yu, Xiaolei Liu, Long He, Paola M. Cavaliere, Andre Chavez, Erik Zhang, Meltem Isik, Anthony Couvillon, Noah E. Dephoure, T. Keith Blackwell, Jane J. Yu, Joshua D. Rabinowitz, Lewis C. Cantley, John Blenis
      mTORC1 is a signal integrator and master regulator of cellular anabolic processes linked to cell growth and survival. Here, we demonstrate that mTORC1 promotes lipid biogenesis via SRPK2, a key regulator of RNA-binding SR proteins. mTORC1-activated S6K1 phosphorylates SRPK2 at Ser494, which primes Ser497 phosphorylation by CK1. These phosphorylation events promote SRPK2 nuclear translocation and phosphorylation of SR proteins. Genome-wide transcriptome analysis reveals that lipid biosynthetic enzymes are among the downstream targets of mTORC1-SRPK2 signaling. Mechanistically, SRPK2 promotes SR protein binding to U1-70K to induce splicing of lipogenic pre-mRNAs. Inhibition of this signaling pathway leads to intron retention of lipogenic genes, which triggers nonsense-mediated mRNA decay. Genetic or pharmacological inhibition of SRPK2 blunts de novo lipid synthesis, thereby suppressing cell growth. These results thus reveal a novel role of mTORC1-SRPK2 signaling in post-transcriptional regulation of lipid metabolism and demonstrate that SRPK2 is a potential therapeutic target for mTORC1-driven metabolic disorders.
      Graphical abstract image Teaser An mTOR-dependent pathway is a key post-transcriptional regulator of lipogenic enzymes that are involved in tumor growth.

      PubDate: 2018-02-15T15:59:20Z
       
  • Oncogenic Role of THOR, a Conserved Cancer/Testis Long Non-coding RNA
    • Abstract: Publication date: 14 December 2017
      Source:Cell, Volume 171, Issue 7
      Author(s): Yasuyuki Hosono, Yashar S. Niknafs, John R. Prensner, Matthew K. Iyer, Saravana M. Dhanasekaran, Rohit Mehra, Sethuramasundaram Pitchiaya, Jean Tien, June Escara-Wilke, Anton Poliakov, Shih-Chun Chu, Sahal Saleh, Keerthana Sankar, Fengyun Su, Shuling Guo, Yuanyuan Qiao, Susan M. Freier, Huynh-Hoa Bui, Xuhong Cao, Rohit Malik, Timothy M. Johnson, David G. Beer, Felix Y. Feng, Weibin Zhou, Arul M. Chinnaiyan
      Large-scale transcriptome sequencing efforts have vastly expanded the catalog of long non-coding RNAs (lncRNAs) with varying evolutionary conservation, lineage expression, and cancer specificity. Here, we functionally characterize a novel ultraconserved lncRNA, THOR (ENSG00000226856), which exhibits expression exclusively in testis and a broad range of human cancers. THOR knockdown and overexpression in multiple cell lines and animal models alters cell or tumor growth supporting an oncogenic role. We discovered a conserved interaction of THOR with IGF2BP1 and show that THOR contributes to the mRNA stabilization activities of IGF2BP1. Notably, transgenic THOR knockout produced fertilization defects in zebrafish and also conferred a resistance to melanoma onset. Likewise, ectopic expression of human THOR in zebrafish accelerated the onset of melanoma. THOR represents a novel class of functionally important cancer/testis lncRNAs whose structure and function have undergone positive evolutionary selection.
      Graphical abstract image Teaser An ultraconserved lncRNA promotes oncogenesis.

      PubDate: 2018-02-15T15:59:20Z
       
  • YY1 Is a Structural Regulator of Enhancer-Promoter Loops
    • Abstract: Publication date: 14 December 2017
      Source:Cell, Volume 171, Issue 7
      Author(s): Abraham S. Weintraub, Charles H. Li, Alicia V. Zamudio, Alla A. Sigova, Nancy M. Hannett, Daniel S. Day, Brian J. Abraham, Malkiel A. Cohen, Behnam Nabet, Dennis L. Buckley, Yang Eric Guo, Denes Hnisz, Rudolf Jaenisch, James E. Bradner, Nathanael S. Gray, Richard A. Young
      There is considerable evidence that chromosome structure plays important roles in gene control, but we have limited understanding of the proteins that contribute to structural interactions between gene promoters and their enhancer elements. Large DNA loops that encompass genes and their regulatory elements depend on CTCF-CTCF interactions, but most enhancer-promoter interactions do not employ this structural protein. Here, we show that the ubiquitously expressed transcription factor Yin Yang 1 (YY1) contributes to enhancer-promoter structural interactions in a manner analogous to DNA interactions mediated by CTCF. YY1 binds to active enhancers and promoter-proximal elements and forms dimers that facilitate the interaction of these DNA elements. Deletion of YY1 binding sites or depletion of YY1 protein disrupts enhancer-promoter looping and gene expression. We propose that YY1-mediated enhancer-promoter interactions are a general feature of mammalian gene control.
      Graphical abstract image Teaser YY1 is a structural regulator of enhancer-promoter interactions and facilitates gene expression.

      PubDate: 2018-02-15T15:59:20Z
       
  • Structure of the Post-catalytic Spliceosome from Saccharomyces cerevisiae
    • Abstract: Publication date: 14 December 2017
      Source:Cell, Volume 171, Issue 7
      Author(s): Rui Bai, Chuangye Yan, Ruixue Wan, Jianlin Lei, Yigong Shi
      Removal of an intron from a pre-mRNA by the spliceosome results in the ligation of two exons in the post-catalytic spliceosome (known as the P complex). Here, we present a cryo-EM structure of the P complex from Saccharomyces cerevisiae at an average resolution of 3.6 Å. The ligated exon is held in the active site through RNA-RNA contacts. Three bases at the 3′ end of the 5′ exon remain anchored to loop I of U5 small nuclear RNA, and the conserved AG nucleotides of the 3′-splice site (3′SS) are specifically recognized by the invariant adenine of the branch point sequence, the guanine base at the 5′ end of the 5′SS, and an adenine base of U6 snRNA. The 3′SS is stabilized through an interaction with the 1585-loop of Prp8. The P complex structure provides a view on splice junction formation critical for understanding the complete splicing cycle.
      Graphical abstract image Teaser Structure of the yeast spliceosome after a splicing reaction shows how the 3′-splice site is recognized and anchored.

      PubDate: 2018-02-15T15:59:20Z
       
  • Visualizing the Assembly Pathway of Nucleolar Pre-60S Ribosomes
    • Abstract: Publication date: 14 December 2017
      Source:Cell, Volume 171, Issue 7
      Author(s): Lukas Kater, Matthias Thoms, Clara Barrio-Garcia, Jingdong Cheng, Sherif Ismail, Yasar Luqman Ahmed, Gert Bange, Dieter Kressler, Otto Berninghausen, Irmgard Sinning, Ed Hurt, Roland Beckmann
      Eukaryotic 60S ribosomal subunits are comprised of three rRNAs and ∼50 ribosomal proteins. The initial steps of their formation take place in the nucleolus, but, owing to a lack of structural information, this process is poorly understood. Using cryo-EM, we solved structures of early 60S biogenesis intermediates at 3.3 Å to 4.5 Å resolution, thereby providing insights into their sequential folding and assembly pathway. Besides revealing distinct immature rRNA conformations, we map 25 assembly factors in six different assembly states. Notably, the Nsa1-Rrp1-Rpf1-Mak16 module stabilizes the solvent side of the 60S subunit, and the Erb1-Ytm1-Nop7 complex organizes and connects through Erb1’s meandering N-terminal extension, eight assembly factors, three ribosomal proteins, and three 25S rRNA domains. Our structural snapshots reveal the order of integration and compaction of the six major 60S domains within early nucleolar 60S particles developing stepwise from the solvent side around the exit tunnel to the central protuberance.
      Graphical abstract image Teaser Cryo-EM analysis of the architecture of pre-60S ribosomes provides insights into the sequential events and intermediate states critical for ribosome assembly, as well as the functions of many associated factors.

      PubDate: 2018-02-15T15:59:20Z
       
  • Single-Cell Transcriptomic Analysis of Primary and Metastatic Tumor
           Ecosystems in Head and Neck Cancer
    • Abstract: Publication date: 14 December 2017
      Source:Cell, Volume 171, Issue 7
      Author(s): Sidharth V. Puram, Itay Tirosh, Anuraag S. Parikh, Anoop P. Patel, Keren Yizhak, Shawn Gillespie, Christopher Rodman, Christina L. Luo, Edmund A. Mroz, Kevin S. Emerick, Daniel G. Deschler, Mark A. Varvares, Ravi Mylvaganam, Orit Rozenblatt-Rosen, James W. Rocco, William C. Faquin, Derrick T. Lin, Aviv Regev, Bradley E. Bernstein
      The diverse malignant, stromal, and immune cells in tumors affect growth, metastasis, and response to therapy. We profiled transcriptomes of ∼6,000 single cells from 18 head and neck squamous cell carcinoma (HNSCC) patients, including five matched pairs of primary tumors and lymph node metastases. Stromal and immune cells had consistent expression programs across patients. Conversely, malignant cells varied within and between tumors in their expression of signatures related to cell cycle, stress, hypoxia, epithelial differentiation, and partial epithelial-to-mesenchymal transition (p-EMT). Cells expressing the p-EMT program spatially localized to the leading edge of primary tumors. By integrating single-cell transcriptomes with bulk expression profiles for hundreds of tumors, we refined HNSCC subtypes by their malignant and stromal composition and established p-EMT as an independent predictor of nodal metastasis, grade, and adverse pathologic features. Our results provide insight into the HNSCC ecosystem and define stromal interactions and a p-EMT program associated with metastasis.
      Graphical abstract image Teaser Single-cell transcriptomic analysis in patients with head and neck squamous cell carcinoma highlights the heterogeneous composition of malignant and non-malignant cells in the tumor microenvironment and associates a partial EMT program with metastasis.

      PubDate: 2018-02-15T15:59:20Z
       
  • A J-Protein Co-chaperone Recruits BiP to Monomerize IRE1 and Repress the
           Unfolded Protein Response
    • Abstract: Publication date: 14 December 2017
      Source:Cell, Volume 171, Issue 7
      Author(s): Niko Amin-Wetzel, Reuben A. Saunders, Maarten J. Kamphuis, Claudia Rato, Steffen Preissler, Heather P. Harding, David Ron
      When unfolded proteins accumulate in the endoplasmic reticulum (ER), the unfolded protein response (UPR) increases ER-protein-folding capacity to restore protein-folding homeostasis. Unfolded proteins activate UPR signaling across the ER membrane to the nucleus by promoting oligomerization of IRE1, a conserved transmembrane ER stress receptor. However, the coupling of ER stress to IRE1 oligomerization and activation has remained obscure. Here, we report that the ER luminal co-chaperone ERdj4/DNAJB9 is a selective IRE1 repressor that promotes a complex between the luminal Hsp70 BiP and the luminal stress-sensing domain of IRE1α (IRE1LD). In vitro, ERdj4 is required for complex formation between BiP and IRE1LD. ERdj4 associates with IRE1LD and recruits BiP through the stimulation of ATP hydrolysis, forcibly disrupting IRE1 dimers. Unfolded proteins compete for BiP and restore IRE1LD to its default, dimeric, and active state. These observations establish BiP and its J domain co-chaperones as key regulators of the UPR.
      Graphical abstract image Teaser Molecular basis for the regulation of the unfolded protein response by chaperones and misfolded proteins.

      PubDate: 2018-02-15T15:59:20Z
       
  • Structural Basis for Regulated Proteolysis by the α-Secretase ADAM10
    • Abstract: Publication date: 14 December 2017
      Source:Cell, Volume 171, Issue 7
      Author(s): Tom C.M. Seegar, Lauren B. Killingsworth, Nayanendu Saha, Peter A. Meyer, Dhabaleswar Patra, Brandon Zimmerman, Peter W. Janes, Eric Rubinstein, Dimitar B. Nikolov, Georgios Skiniotis, Andrew C. Kruse, Stephen C. Blacklow
      Cleavage of membrane-anchored proteins by ADAM (a disintegrin and metalloproteinase) endopeptidases plays a key role in a wide variety of biological signal transduction and protein turnover processes. Among ADAM family members, ADAM10 stands out as particularly important because it is both responsible for regulated proteolysis of Notch receptors and catalyzes the non-amyloidogenic α-secretase cleavage of the Alzheimer’s precursor protein (APP). We present here the X-ray crystal structure of the ADAM10 ectodomain, which, together with biochemical and cellular studies, reveals how access to the enzyme active site is regulated. The enzyme adopts an unanticipated architecture in which the C-terminal cysteine-rich domain partially occludes the enzyme active site, preventing unfettered substrate access. Binding of a modulatory antibody to the cysteine-rich domain liberates the catalytic domain from autoinhibition, enhancing enzymatic activity toward a peptide substrate. Together, these studies reveal a mechanism for regulation of ADAM activity and offer a roadmap for its modulation.
      Graphical abstract image Teaser The X-ray structure of the ADAM10 ectodomain, together with biochemical and cell-based studies, reveals mechanistic insights into its enzymatic function in Notch signaling and in processing of the Alzheimer's precursor protein APP.

      PubDate: 2018-02-15T15:59:20Z
       
  • Neuromodulatory Control of Long-Term Behavioral Patterns and Individuality
           across Development
    • Abstract: Publication date: 14 December 2017
      Source:Cell, Volume 171, Issue 7
      Author(s): Shay Stern, Christoph Kirst, Cornelia I. Bargmann
      Animals generate complex patterns of behavior across development that may be shared or unique to individuals. Here, we examine the contributions of developmental programs and individual variation to behavior by monitoring single Caenorhabditis elegans nematodes over their complete developmental trajectories and quantifying their behavior at high spatiotemporal resolution. These measurements reveal reproducible trajectories of spontaneous foraging behaviors that are stereotyped within and between developmental stages. Dopamine, serotonin, the neuropeptide receptor NPR-1, and the TGF-β peptide DAF-7 each have stage-specific effects on behavioral trajectories, implying the existence of a modular temporal program controlled by neuromodulators. In addition, a fraction of individuals within isogenic populations raised in controlled environments have consistent, non-genetic behavioral biases that persist across development. Several neuromodulatory systems increase or decrease the degree of non-genetic individuality to shape sustained patterns of behavior across the population.
      Graphical abstract image Teaser Individual nematodes exhibit consistent, non-genetic behavioral biases that are impacted by several neuromodulatory systems.

      PubDate: 2018-02-15T15:59:20Z
       
  • Combined Social and Spatial Coding in a Descending Projection from the
           Prefrontal Cortex
    • Abstract: Publication date: 14 December 2017
      Source:Cell, Volume 171, Issue 7
      Author(s): Malavika Murugan, Hee Jae Jang, Michelle Park, Ellia M. Miller, Julia Cox, Joshua P. Taliaferro, Nathan F. Parker, Varun Bhave, Hong Hur, Yupu Liang, Alexander R. Nectow, Jonathan W. Pillow, Ilana B. Witten
      Social behaviors are crucial to all mammals. Although the prelimbic cortex (PL, part of medial prefrontal cortex) has been implicated in social behavior, it is not clear which neurons are relevant or how they contribute. We found that PL contains anatomically and molecularly distinct subpopulations that target three downstream regions that have been implicated in social behavior: the nucleus accumbens (NAc), amygdala, and ventral tegmental area. Activation of NAc-projecting PL neurons (PL-NAc), but not the other subpopulations, decreased the preference for a social target. To determine what information PL-NAc neurons convey, we selectively recorded from them and found that individual neurons were active during social investigation, but only in specific spatial locations. Spatially specific manipulation of these neurons bidirectionally regulated the formation of a social-spatial association. Thus, the unexpected combination of social and spatial information within the PL-NAc may contribute to social behavior by supporting social-spatial learning.
      Graphical abstract image Teaser Prefrontal neurons that project to the accumbens encode a combination of social and spatial information and bidirectionally modulate social-spatial learning.

      PubDate: 2018-02-15T15:59:20Z
       
  • Combination Cancer Therapy Can Confer Benefit via Patient-to-Patient
           Variability without Drug Additivity or Synergy
    • Abstract: Publication date: 14 December 2017
      Source:Cell, Volume 171, Issue 7
      Author(s): Adam C. Palmer, Peter K. Sorger
      Combination cancer therapies aim to improve the probability and magnitude of therapeutic responses and reduce the likelihood of acquired resistance in an individual patient. However, drugs are tested in clinical trials on genetically diverse patient populations. We show here that patient-to-patient variability and independent drug action are sufficient to explain the superiority of many FDA-approved drug combinations in the absence of drug synergy or additivity. This is also true for combinations tested in patient-derived tumor xenografts. In a combination exhibiting independent drug action, each patient benefits solely from the drug to which his or her tumor is most sensitive, with no added benefit from other drugs. Even when drug combinations exhibit additivity or synergy in pre-clinical models, patient-to-patient variability and low cross-resistance make independent action the dominant mechanism in clinical populations. This insight represents a different way to interpret trial data and a different way to design combination therapies.
      Graphical abstract image Teaser Patient-to-patient variability in response to single drugs is sufficient to explain the efficacy of a large number of combination cancer therapies without pharmacologically additive or synergistic effect in individual patients.

      PubDate: 2018-02-15T15:59:20Z
       
  • A Method for the Acute and Rapid Degradation of Endogenous Proteins
    • Abstract: Publication date: 14 December 2017
      Source:Cell, Volume 171, Issue 7
      Author(s): Dean Clift, William A. McEwan, Larisa I. Labzin, Vera Konieczny, Binyam Mogessie, Leo C. James, Melina Schuh
      Methods for the targeted disruption of protein function have revolutionized science and greatly expedited the systematic characterization of genes. Two main approaches are currently used to disrupt protein function: DNA knockout and RNA interference, which act at the genome and mRNA level, respectively. A method that directly alters endogenous protein levels is currently not available. Here, we present Trim-Away, a technique to degrade endogenous proteins acutely in mammalian cells without prior modification of the genome or mRNA. Trim-Away harnesses the cellular protein degradation machinery to remove unmodified native proteins within minutes of application. This rapidity minimizes the risk that phenotypes are compensated and that secondary, non-specific defects accumulate over time. Because Trim-Away utilizes antibodies, it can be applied to a wide range of target proteins using off-the-shelf reagents. Trim-Away allows the study of protein function in diverse cell types, including non-dividing primary cells where genome- and RNA-targeting methods are limited.
      Graphical abstract image

      PubDate: 2018-02-15T15:59:20Z
       
  • Perinatal Licensing of Thermogenesis by IL-33 and ST2
    • Abstract: Publication date: 14 December 2017
      Source:Cell, Volume 171, Issue 7
      Author(s): Justin I. Odegaard, Min-Woo Lee, Yoshitaka Sogawa, Ambre M. Bertholet, Richard M. Locksley, David E. Weinberg, Yuriy Kirichok, Rahul C. Deo, Ajay Chawla


      PubDate: 2018-02-15T15:59:20Z
       
  • SnapShot: Abscisic Acid Signaling
    • Abstract: Publication date: 14 December 2017
      Source:Cell, Volume 171, Issue 7
      Author(s): Felix Hauser, Zixing Li, Rainer Waadt, Julian I. Schroeder
      Abscisic acid is a key phytohormone produced in response to abiotic stress conditions and is an activator of abiotic stress resistance mechanisms and a regulator during diverse developmental stages in plants. This SnapShot explores how ABA signaling operates and coordinates resistance during stress responses and modulates plant development.
      Teaser Abscisic acid is a key phytohormone produced in response to abiotic stress conditions and is an activator of abiotic stress resistance mechanisms and a regulator during diverse developmental stages in plants. This SnapShot explores how ABA signaling operates and coordinates resistance during stress responses and modulates plant development.

      PubDate: 2018-02-15T15:59:20Z
       
  • The Ferrous Awakens
    • Abstract: Publication date: 30 November 2017
      Source:Cell, Volume 171, Issue 6
      Author(s): Andrew J. Rennekamp
      Teaser Recent discoveries provide a new hope that relapses of several types of cancer can be prevented by inducing ferroptosis.

      PubDate: 2018-02-15T15:59:20Z
       
  • How Cryo-EM Became so Hot
    • Abstract: Publication date: 30 November 2017
      Source:Cell, Volume 171, Issue 6
      Author(s): Yifan Cheng, Robert M. Glaeser, Eva Nogales
      The Royal Swedish Academy of Sciences awarded the 2017 Nobel Prize for Chemistry to Jacques Dubochet, Joachim Frank, and Richard Henderson for “developing cryoelectron microscopy for the high-resolution structure determination of biomolecules in solution.” Achieving this goal, which required innovation, persistence, and uncommon physical insight, has broadened horizons for structural studies in molecular and cell biology.
      Teaser The Royal Swedish Academy of Sciences awarded the 2017 Nobel Prize for Chemistry to Jacques Dubochet, Joachim Frank, and Richard Henderson for “developing cryoelectron microscopy for the high-resolution structure determination of biomolecules in solution.” Achieving this goal, which required innovation, persistence, and uncommon physical insight, has broadened horizons for structural studies in molecular and cell biology.

      PubDate: 2018-02-15T15:59:20Z
       
  • Physiology Flies with Time
    • Abstract: Publication date: 30 November 2017
      Source:Cell, Volume 171, Issue 6
      Author(s): Amita Sehgal
      The 2017 Nobel Prize in Medicine or Physiology has been awarded to Jeffrey Hall, Michael Rosbash, and Michael Young for elucidating molecular mechanisms of the circadian clock. From studies beginning in fruit flies, we now know that circadian regulation pervades most biological processes and has strong ties to human health and disease.
      Teaser The 2017 Nobel Prize in Medicine or Physiology has been awarded to Jeffrey Hall, Michael Rosbash, and Michael Young for elucidating molecular mechanisms of the circadian clock. From studies beginning in fruit flies, we now know that circadian regulation pervades most biological processes and has strong ties to human health and disease.

      PubDate: 2018-02-15T15:59:20Z
       
  • As Time Flew By
    • Abstract: Publication date: 30 November 2017
      Source:Cell, Volume 171, Issue 6
      Author(s): Michael W. Young


      PubDate: 2018-02-15T15:59:20Z
       
  • An Element of Life
    • Abstract: Publication date: 25 January 2018
      Source:Cell, Volume 172, Issue 3
      Author(s): Douglas R. Green
      While it has been known for decades that the essential function of selenium was in the form of its incorporation as selenocysteine into selenoproteins—including the enzyme glutathione peroxidase-4—now, Ingold et al. (2018) reveal the precise role of selenolate-based catalysis by this enzyme.
      Teaser While it has been known for decades that the essential function of selenium was in the form of its incorporation as selenocysteine into selenoproteins—including the enzyme glutathione peroxidase-4—now, Ingold et al. (2018) reveal the precise role of selenolate-based catalysis by this enzyme.

      PubDate: 2018-02-05T08:58:01Z
       
  • Meiotic Recombination: Genetics’ Good Old Scalpel
    • Abstract: Publication date: 25 January 2018
      Source:Cell, Volume 172, Issue 3
      Author(s): Shai Slomka, Yitzhak Pilpel
      In the era of genome engineering, a new study returns to classical genetics to decipher genotype-phenotype relationships in unprecedented throughput and with unprecedented accuracy. Capitalizing on natural variation in yeast strains and frequent meiotic recombination, She and Jarosz (2018) dissect and map to nucleotide resolution, simple and complex determinants of diverse phenotypic traits.
      Teaser In the era of genome engineering, a new study returns to classical genetics to decipher genotype-phenotype relationships in unprecedented throughput and with unprecedented accuracy. Capitalizing on natural variation in yeast strains and frequent meiotic recombination, She and Jarosz (2018) dissect and map to nucleotide resolution, simple and complex determinants of diverse phenotypic traits.

      PubDate: 2018-02-05T08:58:01Z
       
  • Functional Classification and Experimental Dissection of Long Noncoding
           RNAs
    • Abstract: Publication date: 25 January 2018
      Source:Cell, Volume 172, Issue 3
      Author(s): Florian Kopp, Joshua T. Mendell
      Over the last decade, it has been increasingly demonstrated that the genomes of many species are pervasively transcribed, resulting in the production of numerous long noncoding RNAs (lncRNAs). At the same time, it is now appreciated that many types of DNA regulatory elements, such as enhancers and promoters, regularly initiate bi-directional transcription. Thus, discerning functional noncoding transcripts from a vast transcriptome is a paramount priority, and challenge, for the lncRNA field. In this review, we aim to provide a conceptual and experimental framework for classifying and elucidating lncRNA function. We categorize lncRNA loci into those that regulate gene expression in cis versus those that perform functions in trans and propose an experimental approach to dissect lncRNA activity based on these classifications. These strategies to further understand lncRNAs promise to reveal new and unanticipated biology with great potential to advance our understanding of normal physiology and disease.
      Teaser Identifying functional noncoding transcripts within a complex transcriptome remains a challenge. This review explores examples of known functional lncRNAs and then presents a framework for unlocking biological insights from new lncRNAs of interest.

      PubDate: 2018-02-05T08:58:01Z
       
  • Intrinsic Immunity Shapes Viral Resistance of Stem Cells
    • Abstract: Publication date: 25 January 2018
      Source:Cell, Volume 172, Issue 3
      Author(s): Xianfang Wu, Viet Loan Dao Thi, Yumin Huang, Eva Billerbeck, Debjani Saha, Hans-Heinrich Hoffmann, Yaomei Wang, Luis A. Vale Silva, Stephanie Sarbanes, Tony Sun, Linda Andrus, Yingpu Yu, Corrine Quirk, Melody Li, Margaret R. MacDonald, William M. Schneider, Xiuli An, Brad R. Rosenberg, Charles M. Rice
      Stem cells are highly resistant to viral infection compared to their differentiated progeny; however, the mechanism is mysterious. Here, we analyzed gene expression in mammalian stem cells and cells at various stages of differentiation. We find that, conserved across species, stem cells express a subset of genes previously classified as interferon (IFN) stimulated genes (ISGs) but that expression is intrinsic, as stem cells are refractory to interferon. This intrinsic ISG expression varies in a cell-type-specific manner, and many ISGs decrease upon differentiation, at which time cells become IFN responsive, allowing induction of a broad spectrum of ISGs by IFN signaling. Importantly, we show that intrinsically expressed ISGs protect stem cells against viral infection. We demonstrate the in vivo importance of intrinsic ISG expression for protecting stem cells and their differentiation potential during viral infection. These findings have intriguing implications for understanding stem cell biology and the evolution of pathogen resistance.
      Graphical abstract image Teaser Intrinsic expression of interferon-stimulated genes makes stem cells resistant to infections, preserving their pool throughout the organism’s lifespan.

      PubDate: 2018-02-05T08:58:01Z
       
  • Mapping Causal Variants with Single-Nucleotide Resolution Reveals
           Biochemical Drivers of Phenotypic Change
    • Abstract: Publication date: 25 January 2018
      Source:Cell, Volume 172, Issue 3
      Author(s): Richard She, Daniel F. Jarosz
      Understanding the sequence determinants that give rise to diversity among individuals and species is the central challenge of genetics. However, despite ever greater numbers of sequenced genomes, most genome-wide association studies cannot distinguish causal variants from linked passenger mutations spanning many genes. We report that this inherent challenge can be overcome in model organisms. By pushing the advantages of inbred crossing to its practical limit in Saccharomyces cerevisiae, we improved the statistical resolution of linkage analysis to single nucleotides. This “super-resolution” approach allowed us to map 370 causal variants across 26 quantitative traits. Missense, synonymous, and cis-regulatory mutations collectively gave rise to phenotypic diversity, providing mechanistic insight into the basis of evolutionary divergence. Our data also systematically unmasked complex genetic architectures, revealing that multiple closely linked driver mutations frequently act on the same quantitative trait. Single-nucleotide mapping thus complements traditional deletion and overexpression screening paradigms and opens new frontiers in quantitative genetics.
      Graphical abstract image Teaser A roadmap is presented for systematically and quantitatively discerning the relationship between genotype and phenotype at the single-nucleotide resolution.

      PubDate: 2018-02-05T08:58:01Z
       
  • Initiation of Antiviral B Cell Immunity Relies on Innate Signals from
           Spatially Positioned NKT Cells
    • Abstract: Publication date: 25 January 2018
      Source:Cell, Volume 172, Issue 3
      Author(s): Mauro Gaya, Patricia Barral, Marianne Burbage, Shweta Aggarwal, Beatriz Montaner, Andrew Warren Navia, Malika Aid, Carlson Tsui, Paula Maldonado, Usha Nair, Khader Ghneim, Padraic G. Fallon, Rafick-Pierre Sekaly, Dan H. Barouch, Alex K. Shalek, Andreas Bruckbauer, Jessica Strid, Facundo D. Batista
      B cells constitute an essential line of defense from pathogenic infections through the generation of class-switched antibody-secreting cells (ASCs) in germinal centers. Although this process is known to be regulated by follicular helper T (TfH) cells, the mechanism by which B cells initially seed germinal center reactions remains elusive. We found that NKT cells, a population of innate-like T lymphocytes, are critical for the induction of B cell immunity upon viral infection. The positioning of NKT cells at the interfollicular areas of lymph nodes facilitates both their direct priming by resident macrophages and the localized delivery of innate signals to antigen-experienced B cells. Indeed, NKT cells secrete an early wave of IL-4 and constitute up to 70% of the total IL-4-producing cells during the initial stages of infection. Importantly, the requirement of this innate immunity arm appears to be evolutionarily conserved because early NKT and IL-4 gene signatures also positively correlate with the levels of neutralizing antibodies in Zika-virus-infected macaques. In conclusion, our data support a model wherein a pre-TfH wave of IL-4 secreted by interfollicular NKT cells triggers the seeding of germinal center cells and serves as an innate link between viral infection and B cell immunity.
      Graphical abstract image Teaser NKT cells are required for the initial formation of germinal centers and production of effective neutralizing antibody responses against viruses.

      PubDate: 2018-02-05T08:58:01Z
       
  • Targeting KRAS Mutant Cancers with a Covalent G12C-Specific Inhibitor
    • Abstract: Publication date: 25 January 2018
      Source:Cell, Volume 172, Issue 3
      Author(s): Matthew R. Janes, Jingchuan Zhang, Lian-Sheng Li, Rasmus Hansen, Ulf Peters, Xin Guo, Yuching Chen, Anjali Babbar, Sarah J. Firdaus, Levan Darjania, Jun Feng, Jeffrey H. Chen, Shuangwei Li, Shisheng Li, Yun O. Long, Carol Thach, Yuan Liu, Ata Zarieh, Tess Ely, Jeff M. Kucharski, Linda V. Kessler, Tao Wu, Ke Yu, Yi Wang, Yvonne Yao, Xiaohu Deng, Patrick P. Zarrinkar, Dirk Brehmer, Dashyant Dhanak, Matthew V. Lorenzi, Dana Hu-Lowe, Matthew P. Patricelli, Pingda Ren, Yi Liu
      KRASG12C was recently identified to be potentially druggable by allele-specific covalent targeting of Cys-12 in vicinity to an inducible allosteric switch II pocket (S-IIP). Success of this approach requires active cycling of KRASG12C between its active-GTP and inactive-GDP conformations as accessibility of the S-IIP is restricted only to the GDP-bound state. This strategy proved feasible for inhibiting mutant KRAS in vitro; however, it is uncertain whether this approach would translate to in vivo. Here, we describe structure-based design and identification of ARS-1620, a covalent compound with high potency and selectivity for KRASG12C. ARS-1620 achieves rapid and sustained in vivo target occupancy to induce tumor regression. We use ARS-1620 to dissect oncogenic KRAS dependency and demonstrate that monolayer culture formats significantly underestimate KRAS dependency in vivo. This study provides in vivo evidence that mutant KRAS can be selectively targeted and reveals ARS-1620 as representing a new generation of KRASG12C-specific inhibitors with promising therapeutic potential.
      Graphical abstract image Teaser A covalent inhibitor specific for G12C mutant KRAS induces tumor regression in in vivo models.

      PubDate: 2018-02-05T08:58:01Z
       
  • Context-Dependent and Disease-Specific Diversity in Protein Interactions
           within Stress Granules
    • Abstract: Publication date: 25 January 2018
      Source:Cell, Volume 172, Issue 3
      Author(s): Sebastian Markmiller, Sahar Soltanieh, Kari L. Server, Raymond Mak, Wenhao Jin, Mark Y. Fang, En-Ching Luo, Florian Krach, Dejun Yang, Anindya Sen, Amit Fulzele, Jacob M. Wozniak, David J. Gonzalez, Mark W. Kankel, Fen-Biao Gao, Eric J. Bennett, Eric Lécuyer, Gene W. Yeo
      Stress granules (SGs) are transient ribonucleoprotein (RNP) aggregates that form during cellular stress and are increasingly implicated in human neurodegeneration. To study the proteome and compositional diversity of SGs in different cell types and in the context of neurodegeneration-linked mutations, we used ascorbate peroxidase (APEX) proximity labeling, mass spectrometry, and immunofluorescence to identify ∼150 previously unknown human SG components. A highly integrated, pre-existing SG protein interaction network in unstressed cells facilitates rapid coalescence into larger SGs. Approximately 20% of SG diversity is stress or cell-type dependent, with neuronal SGs displaying a particularly complex repertoire of proteins enriched in chaperones and autophagy factors. Strengthening the link between SGs and neurodegeneration, we demonstrate aberrant dynamics, composition, and subcellular distribution of SGs in cells from amyotrophic lateral sclerosis (ALS) patients. Using three Drosophila ALS/FTD models, we identify SG-associated modifiers of neurotoxicity in vivo. Altogether, our results highlight SG proteins as central to understanding and ultimately targeting neurodegeneration.
      Graphical abstract image Teaser Interactions between stress granule proteins exist ahead of a stress response and candidate SG proteins modify disease phenotypes in vivo.

      PubDate: 2018-02-05T08:58:01Z
       
  • Nudt21 Controls Cell Fate by Connecting Alternative Polyadenylation to
           Chromatin Signaling
    • Abstract: Publication date: 25 January 2018
      Source:Cell, Volume 172, Issue 3
      Author(s): Justin Brumbaugh, Bruno Di Stefano, Xiuye Wang, Marti Borkent, Elmira Forouzmand, Katie J. Clowers, Fei Ji, Benjamin A. Schwarz, Marian Kalocsay, Stephen J. Elledge, Yue Chen, Ruslan I. Sadreyev, Steven P. Gygi, Guang Hu, Yongsheng Shi, Konrad Hochedlinger


      PubDate: 2018-02-05T08:58:01Z
       
  • SnapShot: O-Glycosylation Pathways across Kingdoms
    • Abstract: Publication date: 25 January 2018
      Source:Cell, Volume 172, Issue 3
      Author(s): Hiren J. Joshi, Yoshiki Narimatsu, Katrine T. Schjoldager, Hanne L.P. Tytgat, Markus Aebi, Henrik Clausen, Adnan Halim
      O-glycosylation is one of the most abundant and diverse types of post-translational modifications of proteins. O-glycans modulate the structure, stability, and function of proteins and serve generalized as well as highly specific roles in most biological processes. This ShapShot presents types of O-glycans found in different organisms and their principle biosynthetic pathways. To view this SnapShot, open or download the PDF.
      Teaser O-glycosylation is one of the most abundant and diverse types of post-translational modifications of proteins. O-glycans modulate the structure, stability, and function of proteins and serve generalized as well as highly specific roles in most biological processes. This ShapShot presents types of O-glycans found in different organisms and their principle biosynthetic pathways. To view this SnapShot, open or download the PDF.

      PubDate: 2018-02-05T08:58:01Z
       
  • Establishment of DNA-DNA Interactions by the Cohesin Ring
    • Abstract: Publication date: Available online 18 January 2018
      Source:Cell
      Author(s): Yasuto Murayama, Catarina P. Samora, Yumiko Kurokawa, Hiroshi Iwasaki, Frank Uhlmann
      The ring-shaped structural maintenance of chromosome (SMC) complexes are multi-subunit ATPases that topologically encircle DNA. SMC rings make vital contributions to numerous chromosomal functions, including mitotic chromosome condensation, sister chromatid cohesion, DNA repair, and transcriptional regulation. They are thought to do so by establishing interactions between more than one DNA. Here, we demonstrate DNA-DNA tethering by the purified fission yeast cohesin complex. DNA-bound cohesin efficiently and topologically captures a second DNA, but only if that is single-stranded DNA (ssDNA). Like initial double-stranded DNA (dsDNA) embrace, second ssDNA capture is ATP-dependent, and it strictly requires the cohesin loader complex. Second-ssDNA capture is relatively labile but is converted into stable dsDNA-dsDNA cohesion through DNA synthesis. Our study illustrates second-DNA capture by an SMC complex and provides a molecular model for the establishment of sister chromatid cohesion.
      Graphical abstract image Teaser Cohesin sets up the initial steps of chromosome cohesion by anchoring single-stranded DNA along to a region of duplex DNA.

      PubDate: 2018-01-25T15:57:07Z
       
  • Ultraconserved Enhancers Are Required for Normal Development
    • Abstract: Publication date: Available online 18 January 2018
      Source:Cell
      Author(s): Diane E. Dickel, Athena R. Ypsilanti, Ramón Pla, Yiwen Zhu, Iros Barozzi, Brandon J. Mannion, Yupar S. Khin, Yoko Fukuda-Yuzawa, Ingrid Plajzer-Frick, Catherine S. Pickle, Elizabeth A. Lee, Anne N. Harrington, Quan T. Pham, Tyler H. Garvin, Momoe Kato, Marco Osterwalder, Jennifer A. Akiyama, Veena Afzal, John L.R. Rubenstein, Len A. Pennacchio, Axel Visel
      Non-coding “ultraconserved” regions containing hundreds of consecutive bases of perfect sequence conservation across mammalian genomes can function as distant-acting enhancers. However, initial deletion studies in mice revealed that loss of such extraordinarily constrained sequences had no immediate impact on viability. Here, we show that ultraconserved enhancers are required for normal development. Focusing on some of the longest ultraconserved sites genome wide, located near the essential neuronal transcription factor Arx, we used genome editing to create an expanded series of knockout mice lacking individual or combinations of ultraconserved enhancers. Mice with single or pairwise deletions of ultraconserved enhancers were viable and fertile but in nearly all cases showed neurological or growth abnormalities, including substantial alterations of neuron populations and structural brain defects. Our results demonstrate the functional importance of ultraconserved enhancers and indicate that remarkably strong sequence conservation likely results from fitness deficits that appear subtle in a laboratory setting.
      Graphical abstract image Teaser Although initial studies suggested that loss of ultraconserved enhancers had no impact on viability, these sequences are now shown to be required for normal development.

      PubDate: 2018-01-25T15:57:07Z
       
  • Structure and Conformational Dynamics of the Human Spliceosomal Bact
           Complex
    • Abstract: Publication date: Available online 17 January 2018
      Source:Cell
      Author(s): David Haselbach, Ilya Komarov, Dmitry E. Agafonov, Klaus Hartmuth, Benjamin Graf, Olexandr Dybkov, Henning Urlaub, Berthold Kastner, Reinhard Lührmann, Holger Stark
      The spliceosome is a highly dynamic macromolecular complex that precisely excises introns from pre-mRNA. Here we report the cryo-EM 3D structure of the human Bact spliceosome at 3.4 Å resolution. In the Bact state, the spliceosome is activated but not catalytically primed, so that it is functionally blocked prior to the first catalytic step of splicing. The spliceosomal core is similar to the yeast Bact spliceosome; important differences include the presence of the RNA helicase aquarius and peptidyl prolyl isomerases. To examine the overall dynamic behavior of the purified spliceosome, we developed a principal component analysis-based approach. Calculating the energy landscape revealed eight major conformational states, which we refined to higher resolution. Conformational differences of the highly flexible structural components between these eight states reveal how spliceosomal components contribute to the assembly of the spliceosome, allowing it to generate a dynamic interaction network required for its subsequent catalytic activation.
      Graphical abstract image Teaser A new approach to analyzing cryo-EM data reports on conformational dynamics in the human spliceosome.

      PubDate: 2018-01-25T15:57:07Z
       
  • GroEL Ring Separation and Exchange in the Chaperonin Reaction
    • Abstract: Publication date: Available online 11 January 2018
      Source:Cell
      Author(s): Xiao Yan, Qiaoyun Shi, Andreas Bracher, Goran Miličić, Amit K. Singh, F. Ulrich Hartl, Manajit Hayer-Hartl
      The bacterial chaperonin GroEL and its cofactor, GroES, form a nano-cage for a single molecule of substrate protein (SP) to fold in isolation. GroEL and GroES undergo an ATP-regulated interaction cycle to close and open the folding cage. GroEL consists of two heptameric rings stacked back to back. Here, we show that GroEL undergoes transient ring separation, resulting in ring exchange between complexes. Ring separation occurs upon ATP-binding to the trans ring of the asymmetric GroEL:7ADP:GroES complex in the presence or absence of SP and is a consequence of inter-ring negative allostery. We find that a GroEL mutant unable to perform ring separation is folding active but populates symmetric GroEL:GroES2 complexes, where both GroEL rings function simultaneously rather than sequentially. As a consequence, SP binding and release from the folding chamber is inefficient, and E. coli growth is impaired. We suggest that transient ring separation is an integral part of the chaperonin mechanism.
      Graphical abstract image Teaser During the substrate-folding cycle of GroEL-GroES, the two GroEL rings separate for effective substrate binding and chaperonin activity.

      PubDate: 2018-01-15T02:35:50Z
       
  • Discovery of Next-Generation Antimicrobials through Bacterial
           Self-Screening of Surface-Displayed Peptide Libraries
    • Abstract: Publication date: Available online 4 January 2018
      Source:Cell
      Author(s): Ashley T. Tucker, Sean P. Leonard, Cory D. DuBois, Gregory A. Knauf, Ashley L. Cunningham, Claus O. Wilke, M. Stephen Trent, Bryan W. Davies
      Peptides have great potential to combat antibiotic resistance. While many platforms can screen peptides for their ability to bind to target cells, there are virtually no platforms that directly assess the functionality of peptides. This limitation is exacerbated when identifying antimicrobial peptides because the phenotype, death, selects against itself and has caused a scientific bottleneck that confines research to a few naturally occurring classes of antimicrobial peptides. We have used this seeming dissonance to develop Surface Localized Antimicrobial Display (SLAY), a platform that allows screening of unlimited numbers of peptides of any length, composition, and structure in a single tube for antimicrobial activity. Using SLAY, we screened ∼800,000 random peptide sequences for antimicrobial function and identified thousands of active sequences, dramatically increasing the number of known antimicrobial sequences. SLAY hits present with different potential mechanisms of peptide action and access to areas of antimicrobial physicochemical space beyond what nature has evolved.
      Graphical abstract image Teaser Identification of antimicrobial peptides with diverse compositions expands the range of efficacious bactericidal agents.

      PubDate: 2018-01-15T02:35:50Z
       
  • Stabilization of Reversed Replication Forks by Telomerase Drives Telomere
           Catastrophe
    • Abstract: Publication date: Available online 28 December 2017
      Source:Cell
      Author(s): Pol Margalef, Panagiotis Kotsantis, Valerie Borel, Roberto Bellelli, Stephanie Panier, Simon J. Boulton
      Telomere maintenance critically depends on the distinct activities of telomerase, which adds telomeric repeats to solve the end replication problem, and RTEL1, which dismantles DNA secondary structures at telomeres to facilitate replisome progression. Here, we establish that reversed replication forks are a pathological substrate for telomerase and the source of telomere catastrophe in Rtel1 −/− cells. Inhibiting telomerase recruitment to telomeres, but not its activity, or blocking replication fork reversal through PARP1 inhibition or depleting UBC13 or ZRANB3 prevents the rapid accumulation of dysfunctional telomeres in RTEL1-deficient cells. In this context, we establish that telomerase binding to reversed replication forks inhibits telomere replication, which can be mimicked by preventing replication fork restart through depletion of RECQ1 or PARG. Our results lead us to propose that telomerase inappropriately binds to and inhibits restart of reversed replication forks within telomeres, which compromises replication and leads to critically short telomeres.
      Graphical abstract image Teaser Telomerase can, paradoxically, contribute to telomere shortening by stabilizing stalled replication forks at chromosome ends.

      PubDate: 2018-01-04T05:31:20Z
       
  • Selenium Utilization by GPX4 Is Required to Prevent Hydroperoxide-Induced
           Ferroptosis
    • Abstract: Publication date: Available online 28 December 2017
      Source:Cell
      Author(s): Irina Ingold, Carsten Berndt, Sabine Schmitt, Sebastian Doll, Gereon Poschmann, Katalin Buday, Antonella Roveri, Xiaoxiao Peng, Florencio Porto Freitas, Tobias Seibt, Lisa Mehr, Michaela Aichler, Axel Walch, Daniel Lamp, Martin Jastroch, Sayuri Miyamoto, Wolfgang Wurst, Fulvio Ursini, Elias S.J. Arnér, Noelia Fradejas-Villar, Ulrich Schweizer, Hans Zischka, José Pedro Friedmann Angeli, Marcus Conrad
      Selenoproteins are rare proteins among all kingdoms of life containing the 21st amino acid, selenocysteine. Selenocysteine resembles cysteine, differing only by the substitution of selenium for sulfur. Yet the actual advantage of selenolate- versus thiolate-based catalysis has remained enigmatic, as most of the known selenoproteins also exist as cysteine-containing homologs. Here, we demonstrate that selenolate-based catalysis of the essential mammalian selenoprotein GPX4 is unexpectedly dispensable for normal embryogenesis. Yet the survival of a specific type of interneurons emerges to exclusively depend on selenocysteine-containing GPX4, thereby preventing fatal epileptic seizures. Mechanistically, selenocysteine utilization by GPX4 confers exquisite resistance to irreversible overoxidation as cells expressing a cysteine variant are highly sensitive toward peroxide-induced ferroptosis. Remarkably, concomitant deletion of all selenoproteins in Gpx4 cys/cys cells revealed that selenoproteins are dispensable for cell viability provided partial GPX4 activity is retained. Conclusively, 200 years after its discovery, a specific and indispensable role for selenium is provided.
      Graphical abstract image Teaser The trace element selenium protects a critical population of interneurons from ferroptotic cell death.

      PubDate: 2018-01-04T05:31:20Z
       
  • Natural Killer Cells Control Tumor Growth by Sensing a Growth Factor
    • Abstract: Publication date: Available online 21 December 2017
      Source:Cell
      Author(s): Alexander D. Barrow, Melissa A. Edeling, Vladimir Trifonov, Jingqin Luo, Piyush Goyal, Benjamin Bohl, Jennifer K. Bando, Albert H. Kim, John Walker, Mary Andahazy, Mattia Bugatti, Laura Melocchi, William Vermi, Daved H. Fremont, Sarah Cox, Marina Cella, Christian Schmedt, Marco Colonna
      Many tumors produce platelet-derived growth factor (PDGF)-DD, which promotes cellular proliferation, epithelial-mesenchymal transition, stromal reaction, and angiogenesis through autocrine and paracrine PDGFRβ signaling. By screening a secretome library, we found that the human immunoreceptor NKp44, encoded by NCR2 and expressed on natural killer (NK) cells and innate lymphoid cells, recognizes PDGF-DD. PDGF-DD engagement of NKp44 triggered NK cell secretion of interferon gamma (IFN)-γ and tumor necrosis factor alpha (TNF-α) that induced tumor cell growth arrest. A distinctive transcriptional signature of PDGF-DD-induced cytokines and the downregulation of tumor cell-cycle genes correlated with NCR2 expression and greater survival in glioblastoma. NKp44 expression in mouse NK cells controlled the dissemination of tumors expressing PDGF-DD more effectively than control mice, an effect enhanced by blockade of the inhibitory receptor CD96 or CpG-oligonucleotide treatment. Thus, while cancer cell production of PDGF-DD supports tumor growth and stromal reaction, it concomitantly activates innate immune responses to tumor expansion.
      Graphical abstract image Teaser The growth factor PDGF-DD, expressed by multiple types of tumors, is a stimulatory ligand for human NK cell receptor NKp44.

      PubDate: 2017-12-24T03:56:47Z
       
  • Antigen Identification for Orphan T Cell Receptors Expressed on
           Tumor-Infiltrating Lymphocytes
    • Abstract: Publication date: Available online 21 December 2017
      Source:Cell
      Author(s): Marvin H. Gee, Arnold Han, Shane M. Lofgren, John F. Beausang, Juan L. Mendoza, Michael E. Birnbaum, Michael T. Bethune, Suzanne Fischer, Xinbo Yang, Raquel Gomez-Eerland, David B. Bingham, Leah V. Sibener, Ricardo A. Fernandes, Andrew Velasco, David Baltimore, Ton N. Schumacher, Purvesh Khatri, Stephen R. Quake, Mark M. Davis, K. Christopher Garcia
      The immune system can mount T cell responses against tumors; however, the antigen specificities of tumor-infiltrating lymphocytes (TILs) are not well understood. We used yeast-display libraries of peptide-human leukocyte antigen (pHLA) to screen for antigens of “orphan” T cell receptors (TCRs) expressed on TILs from human colorectal adenocarcinoma. Four TIL-derived TCRs exhibited strong selection for peptides presented in a highly diverse pHLA-A∗02:01 library. Three of the TIL TCRs were specific for non-mutated self-antigens, two of which were present in separate patient tumors, and shared specificity for a non-mutated self-antigen derived from U2AF2. These results show that the exposed recognition surface of MHC-bound peptides accessible to the TCR contains sufficient structural information to enable the reconstruction of sequences of peptide targets for pathogenic TCRs of unknown specificity. This finding underscores the surprising specificity of TCRs for their cognate antigens and enables the facile indentification of tumor antigens through unbiased screening.
      Graphical abstract image Teaser A new approach for identifying T cell receptor ligands reveals insights into the specificity of tumor-infiltrating lymphocytes.

      PubDate: 2017-12-24T03:56:47Z
       
  • Engineered Sialylation of Pathogenic Antibodies In Vivo Attenuates
           Autoimmune Disease
    • Abstract: Publication date: Available online 21 December 2017
      Source:Cell
      Author(s): Jose D. Pagan, Maya Kitaoka, Robert M. Anthony
      Self-reactive IgGs contribute to the pathology of autoimmune diseases, including systemic lupus erythematosus and rheumatoid arthritis. Paradoxically, IgGs are used to treat inflammatory diseases in the form of high-dose intravenous immunoglobulin (IVIG). Distinct glycoforms on the IgG crystallizable fragment (Fc) dictate these divergent functions. IgG anti-inflammatory activity is attributed to sialylation of the Fc glycan. We therefore sought to convert endogenous IgG to anti-inflammatory mediators in vivo by engineering solubilized glycosyltransferases that attach galactose or sialic acid. When both enzymes were administered in a prophylactic or therapeutic fashion, autoimmune inflammation was markedly attenuated in vivo. The enzymes worked through a similar pathway to IVIG, requiring DC-SIGN, STAT6 signaling, and FcγRIIB. Importantly, sialylation was highly specific to pathogenic IgG at the site of inflammation, driven by local platelet release of nucleotide-sugar donors. These results underscore the therapeutic potential of glycoengineering in vivo.
      Graphical abstract image Teaser Endogenous pathogenic antibodies can be enzymatically converted into anti-inflammatory mediators in inflamed tissues, revealing a new strategy to treat autoimmune diseases.

      PubDate: 2017-12-24T03:56:47Z
       
  • Microbiome Influences Prenatal and Adult Microglia in a Sex-Specific
           Manner
    • Abstract: Publication date: Available online 21 December 2017
      Source:Cell
      Author(s): Morgane Sonia Thion, Donovan Low, Aymeric Silvin, Jinmiao Chen, Pauline Grisel, Jonas Schulte-Schrepping, Ronnie Blecher, Thomas Ulas, Paola Squarzoni, Guillaume Hoeffel, Fanny Coulpier, Eleni Siopi, Friederike Sophie David, Claus Scholz, Foo Shihui, Josephine Lum, Arlaine Anne Amoyo, Anis Larbi, Michael Poidinger, Anne Buttgereit, Pierre-Marie Lledo, Melanie Greter, Jerry Kok Yen Chan, Ido Amit, Marc Beyer, Joachim Ludwig Schultze, Andreas Schlitzer, Sven Pettersson, Florent Ginhoux, Sonia Garel
      Microglia are embryonically seeded macrophages that contribute to brain development, homeostasis, and pathologies. It is thus essential to decipher how microglial properties are temporally regulated by intrinsic and extrinsic factors, such as sexual identity and the microbiome. Here, we found that microglia undergo differentiation phases, discernable by transcriptomic signatures and chromatin accessibility landscapes, which can diverge in adult males and females. Remarkably, the absence of microbiome in germ-free mice had a time and sexually dimorphic impact both prenatally and postnatally: microglia were more profoundly perturbed in male embryos and female adults. Antibiotic treatment of adult mice triggered sexually biased microglial responses revealing both acute and long-term effects of microbiota depletion. Finally, human fetal microglia exhibited significant overlap with the murine transcriptomic signature. Our study shows that microglia respond to environmental challenges in a sex- and time-dependent manner from prenatal stages, with major implications for our understanding of microglial contributions to health and disease.
      Graphical abstract image Teaser Microglia respond to environmental challenges, such as signals from the gut microbiome, in a sex- and time-dependent manner.

      PubDate: 2017-12-24T03:56:47Z
       
 
 
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