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Joo Sang Lee, Lital Adler, Hiren Karathia, Narin Carmel, Shiran Rabinovich, Noam Auslander, Rom Keshet, Noa Stettner, Alon Silberman, Lilach Agemy, Daniel Helbling, Raya Eilam, Qin Sun, Alexander Brandis, Sergey Malitsky, Maxim Itkin, Hila Weiss, Sivan Pinto, Shelly Kalaora, Ronen Levy, Eilon Barnea, Arie Admon, David Dimmock, Noam Stern-Ginossar, Avigdor Scherz, Sandesh C S Nagamani, Miguel Unda, David M Wilson, Ronit Elhasid, Arkaitz Carracedo, Yardena Samuels, Sridhar Hannenhalli, Eytan Ruppin, Ayelet Erez
The urea cycle (UC) is the main pathway by which mammals dispose of waste nitrogen. We find that specific alterations in the expression of most UC enzymes occur in many tumors, leading to a general metabolic hallmark termed "UC dysregulation" (UCD). UCD elicits nitrogen diversion toward carbamoyl-phosphate synthetase2, aspartate transcarbamylase, and dihydrooratase (CAD) activation and enhances pyrimidine synthesis, resulting in detectable changes in nitrogen metabolites in both patient tumors and their bio-fluids...
August 6, 2018: Cell
Krijn K Dijkstra, Chiara M Cattaneo, Fleur Weeber, Myriam Chalabi, Joris van de Haar, Lorenzo F Fanchi, Maarten Slagter, Daphne L van der Velden, Sovann Kaing, Sander Kelderman, Nienke van Rooij, Monique E van Leerdam, Annekatrien Depla, Egbert F Smit, Koen J Hartemink, Rosa de Groot, Monika C Wolkers, Norman Sachs, Petur Snaebjornsson, Kim Monkhorst, John Haanen, Hans Clevers, Ton N Schumacher, Emile E Voest
Cancer immunotherapies have shown substantial clinical activity for a subset of patients with epithelial cancers. Still, technological platforms to study cancer T-cell interactions for individual patients and understand determinants of responsiveness are presently lacking. Here, we establish and validate a platform to induce and analyze tumor-specific T cell responses to epithelial cancers in a personalized manner. We demonstrate that co-cultures of autologous tumor organoids and peripheral blood lymphocytes can be used to enrich tumor-reactive T cells from peripheral blood of patients with mismatch repair-deficient colorectal cancer and non-small-cell lung cancer...
August 3, 2018: Cell
Veronica Rodriguez-Bravo, Raffaella Pippa, Won-Min Song, Marc Carceles-Cordon, Ana Dominguez-Andres, Naoto Fujiwara, Jungreem Woo, Anna P Koh, Adam Ertel, Ravi K Lokareddy, Alvaro Cuesta-Dominguez, Rosa S Kim, Irene Rodriguez-Fernandez, Peiyao Li, Ronald Gordon, Hadassa Hirschfield, Josep M Prats, E Premkumar Reddy, Alessandro Fatatis, Daniel P Petrylak, Leonard Gomella, W Kevin Kelly, Scott W Lowe, Karen E Knudsen, Matthew D Galsky, Gino Cingolani, Amaia Lujambio, Yujin Hoshida, Josep Domingo-Domenech
Nuclear pore complexes (NPCs) regulate nuclear-cytoplasmic transport, transcription, and genome integrity in eukaryotic cells. However, their functional roles in cancer remain poorly understood. We interrogated the evolutionary transcriptomic landscape of NPC components, nucleoporins (Nups), from primary to advanced metastatic human prostate cancer (PC). Focused loss-of-function genetic screen of top-upregulated Nups in aggressive PC models identified POM121 as a key contributor to PC aggressiveness. Mechanistically, POM121 promoted PC progression by enhancing importin-dependent nuclear transport of key oncogenic (E2F1, MYC) and PC-specific (AR-GATA2) transcription factors, uncovering a pharmacologically targetable axis that, when inhibited, decreased tumor growth, restored standard therapy efficacy, and improved survival in patient-derived pre-clinical models...
August 3, 2018: Cell
Qianhui Qu, Yoh-Hei Takahashi, Yidai Yang, Hongli Hu, Yan Zhang, Joseph S Brunzelle, Jean-Francois Couture, Ali Shilatifard, Georgios Skiniotis
The methylation of histone 3 lysine 4 (H3K4) is carried out by an evolutionarily conserved family of methyltransferases referred to as complex of proteins associated with Set1 (COMPASS). The activity of the catalytic SET domain (su(var)3-9, enhancer-of-zeste, and trithorax) is endowed through forming a complex with a set of core proteins that are widely shared from yeast to humans. We obtained cryo-electron microscopy (cryo-EM) maps of the yeast Set1/COMPASS core complex at overall 4.0- to 4.4-Å resolution, providing insights into its structural organization and conformational dynamics...
August 3, 2018: Cell
Tao Yu, Yongjin J Zhou, Mingtao Huang, Quanli Liu, Rui Pereira, Florian David, Jens Nielsen
Engineering microorganisms for production of fuels and chemicals often requires major re-programming of metabolism to ensure high flux toward the product of interest. This is challenging, as millions of years of evolution have resulted in establishment of tight regulation of metabolism for optimal growth in the organism's natural habitat. Here, we show through metabolic engineering that it is possible to alter the metabolism of Saccharomyces cerevisiae from traditional ethanol fermentation to a pure lipogenesis metabolism, resulting in high-level production of free fatty acids...
August 2, 2018: Cell
Peng Zhang, Hong Lu, Rui T Peixoto, Mary K Pines, Yuan Ge, Shinichiro Oku, Tabrez J Siddiqui, Yicheng Xie, Wenlan Wu, Stephanie Archer-Hartmann, Keitaro Yoshida, Kenji F Tanaka, A Radu Aricescu, Parastoo Azadi, Michael D Gordon, Bernardo L Sabatini, Rachel O L Wong, Ann Marie Craig
Synapses are fundamental units of communication in the brain. The prototypical synapse-organizing complex neurexin-neuroligin mediates synapse development and function and is central to a shared genetic risk pathway in autism and schizophrenia. Neurexin's role in synapse development is thought to be mediated purely by its protein domains, but we reveal a requirement for a rare glycan modification. Mice lacking heparan sulfate (HS) on neurexin-1 show reduced survival, as well as structural and functional deficits at central synapses...
August 2, 2018: Cell
David Balchin, Goran Miličić, Mike Strauss, Manajit Hayer-Hartl, F Ulrich Hartl
The hetero-oligomeric chaperonin of eukarya, TRiC, is required to fold the cytoskeletal protein actin. The simpler bacterial chaperonin system, GroEL/GroES, is unable to mediate actin folding. Here, we use spectroscopic and structural techniques to determine how TRiC promotes the conformational progression of actin to the native state. We find that actin fails to fold spontaneously even in the absence of aggregation but populates a kinetically trapped, conformationally dynamic state. Binding of this frustrated intermediate to TRiC specifies an extended topology of actin with native-like secondary structure...
August 2, 2018: Cell
Karina K Sanchez, Grischa Y Chen, Alexandria M Palaferri Schieber, Samuel E Redford, Maxim N Shokhirev, Mathias Leblanc, Yujung M Lee, Janelle S Ayres
Pathogen virulence exists on a continuum. The strategies that drive symptomatic or asymptomatic infections remain largely unknown. We took advantage of the concept of lethal dose 50 (LD50) to ask which component of individual non-genetic variation between hosts defines whether they survive or succumb to infection. Using the enteric pathogen Citrobacter, we found no difference in pathogen burdens between healthy and symptomatic populations. Iron metabolism-related genes were induced in asymptomatic hosts compared to symptomatic or naive mice...
July 31, 2018: Cell
Yury Goltsev, Nikolay Samusik, Julia Kennedy-Darling, Salil Bhate, Matthew Hale, Gustavo Vazquez, Sarah Black, Garry P Nolan
A highly multiplexed cytometric imaging approach, termed co-detection by indexing (CODEX), is used here to create multiplexed datasets of normal and lupus (MRL/lpr) murine spleens. CODEX iteratively visualizes antibody binding events using DNA barcodes, fluorescent dNTP analogs, and an in situ polymerization-based indexing procedure. An algorithmic pipeline for single-cell antigen quantification in tightly packed tissues was developed and used to overlay well-known morphological features with de novo characterization of lymphoid tissue architecture at a single-cell and cellular neighborhood levels...
July 31, 2018: Cell
Jan Attig, Federico Agostini, Clare Gooding, Anob M Chakrabarti, Aarti Singh, Nejc Haberman, Julian A Zagalak, Warren Emmett, Christopher W J Smith, Nicholas M Luscombe, Jernej Ule
Long mammalian introns make it challenging for the RNA processing machinery to identify exons accurately. We find that LINE-derived sequences (LINEs) contribute to this selection by recruiting dozens of RNA-binding proteins (RBPs) to introns. This includes MATR3, which promotes binding of PTBP1 to multivalent binding sites within LINEs. Both RBPs repress splicing and 3' end processing within and around LINEs. Notably, repressive RBPs preferentially bind to evolutionarily young LINEs, which are located far from exons...
July 31, 2018: Cell
Shuohao Sun, Travis Babola, Gabriela Pregernig, Kathy S So, Matthew Nguyen, Shin-San M Su, Adam T Palermo, Dwight E Bergles, Joseph C Burns, Ulrich Müller
Type I spiral ganglion neurons (SGNs) transmit sound information from cochlear hair cells to the CNS. Using transcriptome analysis of thousands of single neurons, we demonstrate that murine type I SGNs consist of subclasses that are defined by the expression of subsets of transcription factors, cell adhesion molecules, ion channels, and neurotransmitter receptors. Subtype specification is initiated prior to the onset of hearing during the time period when auditory circuits mature. Gene mutations linked to deafness that disrupt hair cell mechanotransduction or glutamatergic signaling perturb the firing behavior of SGNs prior to hearing onset and disrupt SGN subtype specification...
July 30, 2018: Cell
Brikha R Shrestha, Chester Chia, Lorna Wu, Sharon G Kujawa, M Charles Liberman, Lisa V Goodrich
In the auditory system, type I spiral ganglion neurons (SGNs) convey complex acoustic information from inner hair cells (IHCs) to the brainstem. Although SGNs exhibit variation in physiological and anatomical properties, it is unclear which features are endogenous and which reflect input from synaptic partners. Using single-cell RNA sequencing, we derived a molecular classification of mouse type I SGNs comprising three subtypes that express unique combinations of Ca2+ binding proteins, ion channel regulators, guidance molecules, and transcription factors...
July 28, 2018: Cell
Elizabeth Grace Atkinson, Amanda Jane Audesse, Julia Adela Palacios, Dean Michael Bobo, Ashley Elizabeth Webb, Sohini Ramachandran, Brenna Mariah Henn
FOXP2, initially identified for its role in human speech, contains two nonsynonymous substitutions derived in the human lineage. Evidence for a recent selective sweep in Homo sapiens, however, is at odds with the presence of these substitutions in archaic hominins. Here, we comprehensively reanalyze FOXP2 in hundreds of globally distributed genomes to test for recent selection. We do not find evidence of recent positive or balancing selection at FOXP2. Instead, the original signal appears to have been due to sample composition...
July 27, 2018: Cell
Nam Chu, Antonieta L Salguero, Albert Z Liu, Zan Chen, Daniel R Dempsey, Scott B Ficarro, William M Alexander, Jarrod A Marto, Yana Li, L Mario Amzel, Sandra B Gabelli, Philip A Cole
Akt is a critical protein kinase that drives cancer proliferation, modulates metabolism, and is activated by C-terminal phosphorylation. The current structural model for Akt activation by C-terminal phosphorylation has centered on intramolecular interactions between the C-terminal tail and the N lobe of the kinase domain. Here, we employ expressed protein ligation to produce site-specifically phosphorylated forms of purified Akt1 that are well suited for mechanistic analysis. Using biochemical, crystallographic, and cellular approaches, we determine that pSer473-Akt activation is driven by an intramolecular interaction between the C-tail and the pleckstrin homology (PH)-kinase domain linker that relieves PH domain-mediated Akt1 autoinhibition...
July 27, 2018: Cell
Agnieszka Krzyzosiak, Anna Sigurdardottir, Laura Luh, Marta Carrara, Indrajit Das, Kim Schneider, Anne Bertolotti
Protein phosphorylation is a prevalent and ubiquitous mechanism of regulation. Kinases are popular drug targets, but identifying selective phosphatase inhibitors has been challenging. Here, we used surface plasmon resonance to design a method to enable target-based discovery of selective serine/threonine phosphatase inhibitors. The method targeted a regulatory subunit of protein phosphatase 1, PPP1R15B (R15B), a negative regulator of proteostasis. This yielded Raphin1, a selective inhibitor of R15B. In cells, Raphin1 caused a rapid and transient accumulation of its phosphorylated substrate, resulting in a transient attenuation of protein synthesis...
July 26, 2018: Cell
Peter L Hsu, Heng Li, Ho-Tak Lau, Calvin Leonen, Abhinav Dhall, Shao-En Ong, Champak Chatterjee, Ning Zheng
The SET1/MLL family of histone methyltransferases is conserved in eukaryotes and regulates transcription by catalyzing histone H3K4 mono-, di-, and tri-methylation. These enzymes form a common five-subunit catalytic core whose assembly is critical for their basal and regulated enzymatic activities through unknown mechanisms. Here, we present the crystal structure of the intact yeast COMPASS histone methyltransferase catalytic module consisting of Swd1, Swd3, Bre2, Sdc1, and Set1. The complex is organized by Swd1, whose conserved C-terminal tail not only nucleates Swd3 and a Bre2-Sdc1 subcomplex, but also joins Set1 to construct a regulatory pocket next to the catalytic site...
July 25, 2018: Cell
Menglong Zeng, Xudong Chen, Dongshi Guan, Jia Xu, Haowei Wu, Penger Tong, Mingjie Zhang
Synapses are semi-membraneless, protein-dense, sub-micron chemical reaction compartments responsible for signal processing in each and every neuron. Proper formation and dynamic responses to stimulations of synapses, both during development and in adult, are fundamental to functions of mammalian brains, although the molecular basis governing formation and modulation of compartmentalized synaptic assemblies is unclear. Here, we used a biochemical reconstitution approach to show that, both in solution and on supported membrane bilayers, multivalent interaction networks formed by major excitatory postsynaptic density (PSD) scaffold proteins led to formation of PSD-like assemblies via phase separation...
July 25, 2018: Cell
Anthony Tubbs, Sriram Sridharan, Niek van Wietmarschen, Yaakov Maman, Elsa Callen, Andre Stanlie, Wei Wu, Xia Wu, Amanda Day, Nancy Wong, Mianmian Yin, Andres Canela, Haiqing Fu, Christophe Redon, Steven C Pruitt, Yan Jaszczyszyn, Mirit I Aladjem, Peter D Aplan, Olivier Hyrien, André Nussenzweig
Replication origins, fragile sites, and rDNA have been implicated as sources of chromosomal instability. However, the defining genomic features of replication origins and fragile sites are among the least understood elements of eukaryote genomes. Here, we map sites of replication initiation and breakage in primary cells at high resolution. We find that replication initiates between transcribed genes within nucleosome-depleted structures established by long asymmetrical poly(dA:dT) tracts flanking the initiation site...
July 24, 2018: Cell
Richard Janissen, Mathia M A Arens, Natalia N Vtyurina, Zaïda Rivai, Nicholas D Sunday, Behrouz Eslami-Mossallam, Alexey A Gritsenko, Liedewij Laan, Dick de Ridder, Irina Artsimovitch, Nynke H Dekker, Elio A Abbondanzieri, Anne S Meyer
In stationary-phase Escherichia coli, Dps (DNA-binding protein from starved cells) is the most abundant protein component of the nucleoid. Dps compacts DNA into a dense complex and protects it from damage. Dps has also been proposed to act as a global regulator of transcription. Here, we directly examine the impact of Dps-induced compaction of DNA on the activity of RNA polymerase (RNAP). Strikingly, deleting the dps gene decompacted the nucleoid but did not significantly alter the transcriptome and only mildly altered the proteome during stationary phase...
July 21, 2018: Cell
Lu Wang, Kun Dou, Sungjin Moon, Frederick J Tan, Zz Zhao Zhang
Although animals have evolved multiple mechanisms to suppress transposons, "leaky" mobilizations that cause mutations and diseases still occur. This suggests that transposons employ specific tactics to accomplish robust propagation. By directly tracking mobilization, we show that, during a short and specific time window of oogenesis, retrotransposons achieve massive amplification via a cell-type-specific targeting strategy. Retrotransposons rarely mobilize in undifferentiated germline stem cells. However, as oogenesis proceeds, they utilize supporting nurse cells-which are highly polyploid and eventually undergo apoptosis-as factories to massively manufacture invading products...
July 20, 2018: Cell
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