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  • Location, location, and location: compartmentalization of Hedgehog signaling at primary cilia
    1. Ganesh V Pusapati (ganesh22{at}stanford.edu) 1 and
    2. Rajat Rohatgi (rrohatgi{at}stanford.edu) 1
    1. 1Departments of Medicine and Biochemistry, Stanford University School of Medicine, Stanford, CA, USA

    Primary cilia are solitary, microtubule‐based organelles that serve as signaling hubs for the Hedgehog (Hh) pathway, which regulates embryonic development and adult tissue homeostasis. While protein localization studies have suggested that the dynamic trafficking of Hh components at cilia plays an important role, the molecular basis of Hh signal transduction at cilia is not well understood. In a recent study published in Nature Cell Biology (He et al, 2014), He and colleagues demonstrate that the kinesin KIF7, a conserved regulator of Hh signaling, limits ciliary length by acting at the plus‐ends of microtubules to both reduce growth rate and increase catastrophe frequency. They propose that this biochemical activity establishes a specialized compartment at the tip of the cilia where the activity the Gli family of Hh transcription factors is regulated.

    See also: M He et al

    KIF7 is a conserved kinesin involved in Hh signaling that associates with microtubule plus‐ends in cilia to regulate axonemal stability and length, and to generate a cilia‐tip compartment where Gli proteins processing is regulated.

    Ganesh V Pusapati, Rajat Rohatgi
  • Sharpening rhomboid specificity by dimerisation and allostery
    1. Kvido Strisovsky (kvido.strisovsky{at}uochb.cas.cz) 1 and
    2. Matthew Freeman2
    1. 1Institute of Organic Chemistry and Biochemistry, Academy of Sciences of the Czech Republic, Prague, Czech Republic
    2. 2Dunn School of Pathology University of Oxford, Oxford, UK

    In this issue of The EMBO Journal, mechanistic analyses of substrate cleavage by rhomboid intramembrane proteases suggest that catalytic efficiency towards natural, transmembrane substrates is allosterically stimulated by initial substrate interaction with an intramembrane exosite, whose formation depends on rhomboid dimerisation. In the realm of intramembrane proteolysis, dimerisation and allosteric cooperativity represent new concepts that, once confirmed more broadly, should radically alter our view of how these proteases work.

    See also: E Arutyunova et al

    The finding that allosteric cooperation between rhomboid protease dimers aids specific recognition of physiological substrates offers new concepts in the understanding of intramembrane proteolysis.

    Kvido Strisovsky, Matthew Freeman
  • Genome‐wide siRNA screen reveals coupling between mitotic apoptosis and adaptation
    1. Laura A Díaz‐Martínez1,
    2. Zemfira N Karamysheva14,
    3. Ross Warrington1,
    4. Bing Li1,
    5. Shuguang Wei2,
    6. Xian‐Jin Xie3,
    7. Michael G Roth2 and
    8. Hongtao Yu*,1
    1. 1Department of Pharmacology, Howard Hughes Medical Institute, University of Texas Southwestern Medical Center, Dallas, TX, USA
    2. 2Department of Biochemistry, University of Texas Southwestern Medical Center, Dallas, TX, USA
    3. 3Center for Biostatistics and Clinical Science, University of Texas Southwestern Medical Center, Dallas, TX, USA
    4. 4 Department of Physiology, University of Texas Southwestern Medical Center, Dallas, TX, USA
    1. *Corresponding author. Tel: +1 214 645 6161; Fax: +1 214 645 6156; E‐mail: hongtao.yu{at}utsouthwestern.edu

    An RNAi screen offers new insights into the regulatory networks governing the fate of cancer cells undergoing prolonged drug‐induced mitotic checkpoint arrest.

    Synopsis

    Prolonged mitotic arrest induced by anti‐proliferative drugs eventually results in apoptotic cell death or in mitotic exit due to checkpoint adaptation. An RNAi screen in human cancer cells lines offers new insights into the regulatory networks underlying these processes.

    • Genome‐wide siRNA screen identifies regulators of mitotic cell death and checkpoint adaptation.

    • The BH3‐only protein Noxa promotes apoptosis during mitotic arrest.

    • The spindle checkpoint regulator p31comet suppresses mitotic adaptation and facilitates apoptosis.

    • A Bax/Bak mitochondrial module couples mitotic apoptosis and adaptation.

    • The mitochondrial fission factor Drp1 promotes mitotic checkpoint adaptation.

    • apoptosis
    • mitochondria
    • mitosis
    • mitotic slippage
    • the spindle checkpoint
    • Received January 3, 2014.
    • Revision received May 23, 2014.
    • Accepted June 18, 2014.
    Laura A Díaz‐Martínez, Zemfira N Karamysheva, Ross Warrington, Bing Li, Shuguang Wei, Xian‐Jin Xie, Michael G Roth, Hongtao Yu
  • K‐Lysine acetyltransferase 2a regulates a hippocampal gene expression network linked to memory formation
    1. Roman M Stilling16,
    2. Raik Rönicke2,,
    3. Eva Benito3,,
    4. Hendrik Urbanke3,
    5. Vincenzo Capece4,
    6. Susanne Burkhardt3,
    7. Sanaz Bahari‐Javan3,
    8. Jonas Barth3,
    9. Farahnaz Sananbenesi1,
    10. Anna L Schütz4,
    11. Jerzy Dyczkowski4,
    12. Ana Martinez‐Hernandez3,
    13. Cemil Kerimoglu17,
    14. Sharon YR Dent5,
    15. Stefan Bonn4,
    16. Klaus G Reymann2 and
    17. Andre Fischer*,1,3
    1. 1Department of Psychiatry and Psychotherapy, University Medical Center, Göttingen, Germany
    2. 2Research group for Pathophysiology in Dementia, German Center for Neurodegenerative Diseases (DZNE), Magdeburg, Germany
    3. 3Research group for Epigenetics in Neurodegenerative Diseases, German Center for Neurodegenerative Diseases (DZNE), Göttingen, Germany
    4. 4Research group for Computational Analysis of Biological Networks, German Center for Neurodegenerative Diseases (DZNE), Göttingen, Germany
    5. 5MD Anderson Cancer Center, University of Texas, Smithville, TX, USA
    6. 6 Laboratory for Neurogastroenterology, Alimentary Pharmabiotic Centre (APC), University College Cork, Cork, Ireland
    7. 7 Department Biology II, Anthropology and Human Genetics, Ludwig‐Maximilians University Munich, Martinsried, Germany
    1. *Corresponding author. Tel: +1 (512) 237 9401; E‐mail: afische2{at}gwdg.de
    1. These authors contributed equally to this work

    The histone acetyltransferase KAT2A emerges as a novel key regulator of hippocampal memory consolidation in mice, controlling gene expression linked to neuroactive ligand–receptor signaling in association with NF‐κB.

    Synopsis

    The histone acetyltransferase KAT2A is a novel key regulator of hippocampal memory consolidation in mice, controlling gene expression linked to neuroactive ligand–receptor signaling in association with NF‐κB.

    • KAT2A is the most highly expressed HAT in the hippocampal CA1 region

    • KAT2A is required for memory function

    • KAT2A regulates a gene expression program linked to neuroactive receptor signaling.

    • KAT2A regulates hippocampal gene expression via a mechanisms that involves acetylation of NF‐κB

    • epigenetics
    • histone acetylation
    • histone acetyltransferases
    • learning
    • memory
    • Received January 8, 2014.
    • Revision received May 11, 2014.
    • Accepted June 12, 2014.
    Roman M Stilling, Raik Rönicke, Eva Benito, Hendrik Urbanke, Vincenzo Capece, Susanne Burkhardt, Sanaz Bahari‐Javan, Jonas Barth, Farahnaz Sananbenesi, Anna L Schütz, Jerzy Dyczkowski, Ana Martinez‐Hernandez, Cemil Kerimoglu, Sharon YR Dent, Stefan Bonn, Klaus G Reymann, Andre Fischer
  • Integration of microenvironmental and stress signaling antagonizes colorectal cancer progression
    1. Nina Linde1,
    2. Maria Soledad Sosa1 and
    3. Julio A Aguirre‐Ghiso (julio.aguirre-ghiso{at}mssm.edu) 1
    1. 1Division of Hematology and Oncology, Department of Medicine, Department of Otolaryngology, Tisch Cancer Institute, Black Family Stem Cell Institute, Mount Sinai School of Medicine, New York, NY, USA

    Genetic alterations can drive oncogenic events and cancer development. However, this is only half of the story. It is now evident that tumor progression only occurs if powerful stress signaling pathways and microenvironmental signals are overcome. Two recent Nature Cell Biology papers study how niche signals of primary and target organ barriers have to be overridden for oncogenes to allow for colorectal cancer (CRC) initiation and metastasis (Urosevic et al, 2014; Whissell et al, 2014).

    See also: G Whissell et al (July 2014) and

    J Urosevic et al (July 2014)

    Two recent papers in NCB elucidate stromal signals and intrinsic cellular stress pathways as critical barriers for tumor progression and metastasis, respectively.

    Nina Linde, Maria Soledad Sosa, Julio A Aguirre‐Ghiso
  • A virus capsid‐like nanocompartment that stores iron and protects bacteria from oxidative stress
    1. Colleen A McHugh14,
    2. Juan Fontana2,,
    3. Daniel Nemecek25,
    4. Naiqian Cheng2,
    5. Anastasia A Aksyuk2,
    6. J Bernard Heymann2,
    7. Dennis C Winkler2,
    8. Alan S Lam1,
    9. Joseph S Wall3,
    10. Alasdair C Steven*,2 and
    11. Egbert Hoiczyk*,1
    1. 1W. Harry Feinstone Department of Molecular Microbiology and Immunology, Johns Hopkins Bloomberg School of Public Health, Baltimore, MD, USA
    2. 2Laboratory of Structural Biology Research, National Institute of Arthritis, Musculoskeletal and Skin Diseases, Bethesda, MD, USA
    3. 3Department of Biology, Brookhaven National Laboratory, Upton, NY, USA
    4. 4 Department of Biology and Biological Engineering, California Institute of Technology, Pasadena, CA, USA
    5. 5 Central European Institute of Technology, Masaryk University, Brno, Czech Republic
    1. * Corresponding author. Tel: +1 301 496 0132; Fax: +1 301 443 7651; E‐mail: stevena{at}mail.nih.gov

      Corresponding author. Tel: +1 412 648 8788; Fax: +1 410 955 0105; E‐mail: ehoiczyk{at}jhsph.edu

    1. These two authors contributed equally

    Bacteria compartmentalize by sequestering components into protein shells. Here, such a nanocompartment is shown to structurally resemble virus capsids and to store large amounts of iron for protection under starvation conditions.

    Synopsis

    Bacteria compartmentalize by sequestering components into protein shells. Here, such a nanocompartment is shown to structurally resemble virus capsids and to store large amounts of iron for protection under starvation conditions.

    • Iron homeostasis in Myxococcus xanthus involves iron sequestration into large protein shells (encapsulin nanocompartments).

    • The shell is lined with adaptor proteins with ferritin‐like folds that nucleate iron‐rich granules.

    • The encapsulin system appears to complement a ferritin system.

    • The encapsulin shell closely resembles capsids of bacteriophages and herpesvirus.

    • Thus, phages may have arisen from cellular genes, or M. xanthus may have acquired the encapsulin shell gene from a bacteriophage.

    • cryo‐electron microscopy
    • encapsulin
    • ferritin
    • HK97 fold
    • oxidative stress
    • Received March 24, 2014.
    • Revision received May 9, 2014.
    • Accepted May 27, 2014.
    Colleen A McHugh, Juan Fontana, Daniel Nemecek, Naiqian Cheng, Anastasia A Aksyuk, J Bernard Heymann, Dennis C Winkler, Alan S Lam, Joseph S Wall, Alasdair C Steven, Egbert Hoiczyk
  • The NB‐LRR proteins RGA4 and RGA5 interact functionally and physically to confer disease resistance
    1. Stella Césari1,2,3,,
    2. Hiroyuki Kanzaki4,,
    3. Tadashi Fujiwara5,,
    4. Maud Bernoux3,
    5. Véronique Chalvon1,2,
    6. Yoji Kawano5,
    7. Ko Shimamoto5,,
    8. Peter Dodds3,
    9. Ryohei Terauchi4 and
    10. Thomas Kroj*,1,2
    1. 1INRA UMR BGPI, Montpellier, France
    2. 2CIRAD UMR BGPI, Montpellier, France
    3. 3CSIRO Plant Industry, Canberra, ACT, Australia
    4. 4Iwate Biotechnology Research Center, Kitakami Iwate, Japan
    5. 5Laboratory of Plant Molecular Genetics, Nara Institute of Science and Technology, Takayama Ikoma, Japan
    1. *Corresponding author. Tel: +33 4 99 62 48 62; E‐mail: thomas.kroj{at}supagro.inra.fr
    1. These authors contributed equally to this work

    Plant microbial resistance is mediated by a pair of interacting immune sensors, RGA4 and RGA5. RGA4 mediates cell death but is repressed by RGA5. The repressor is neutralized by binding of pathogen‐derived proteins to the dimer.

    Synopsis

    Plant microbial resistance is mediated by a pair of interacting immune sensors, RGA4 and RGA5. RGA4 mediates cell death but is repressed by RGA5. The repressor is neutralized by binding of pathogen‐derived proteins to the dimer.

    • Rice NB‐LRR pair RGA4 and RGA5 interact through their CC domains and form homo‐ and hetero‐complexes.

    • RGA4 triggers effector‐independent resistance responses that are repressed by RGA5.

    • Recognition and physical binding of the fungal effector protein AVR‐Pia by RGA5 relieves repression and activates RGA4‐dependent resistance signaling.

    • Magnaporthe oryzae
    • pathogen recognition
    • plant immunity
    • resistance protein
    • rice
    • Received January 26, 2014.
    • Revision received May 20, 2014.
    • Accepted June 5, 2014.
    Stella Césari, Hiroyuki Kanzaki, Tadashi Fujiwara, Maud Bernoux, Véronique Chalvon, Yoji Kawano, Ko Shimamoto, Peter Dodds, Ryohei Terauchi, Thomas Kroj