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  • A secretagogin locus of the mammalian hypothalamus controls stress hormone release
    1. Roman A Romanov1,2,,
    2. Alán Alpár*,115,
    3. Ming‐Dong Zhang1,2,
    4. Amit Zeisel1,
    5. André Calas3,
    6. Marc Landry3,
    7. Matthew Fuszard4,
    8. Sally L Shirran4,
    9. Robert Schnell1,
    10. Árpád Dobolyi5,
    11. Márk Oláh6,
    12. Lauren Spence7,
    13. Jan Mulder2,8,
    14. Henrik Martens9,
    15. Miklós Palkovits10,
    16. Mathias Uhlen11,
    17. Harald H Sitte12,
    18. Catherine H Botting4,
    19. Ludwig Wagner13,
    20. Sten Linnarsson1,
    21. Tomas Hökfelt2, and
    22. Tibor Harkany*,1,14,
    1. 1Department of Medical Biochemistry & Biophysics, Karolinska Institutet, Stockholm, Sweden
    2. 2Department of Neuroscience, Karolinska Institutet, Stockholm, Sweden
    3. 3Laboratory for Central Mechanisms of Pain Sensitization, Interdisciplinary Institute for Neuroscience, CNRS UMR 5297 Université Bordeaux 2, Bordeaux, France
    4. 4School of Chemistry, University of St. Andrews, St. Andrews, UK
    5. 5Department of Anatomy, Semmelweis University, Budapest, Hungary
    6. 6Department of Human Morphology and Developmental Biology, Semmelweis University, Budapest, Hungary
    7. 7Institute of Medical Sciences, University of Aberdeen, Aberdeen, UK
    8. 8Science for Life Laboratory, Karolinska Institutet, Stockholm, Sweden
    9. 9Synaptic Systems GmbH, Göttingen, Germany
    10. 10Human Brain Tissue Bank and Laboratory, Semmelweis University, Budapest, Hungary
    11. 11Science for Life Laboratory, Albanova University Center, Royal Institute of Technology, Stockholm, Sweden
    12. 12Center for Physiology and Pharmacology, Institute of Pharmacology Medical University of Vienna, Vienna, Austria
    13. 13University Clinic for Internal Medicine III General Hospital Vienna, Vienna, Austria
    14. 14Department of Molecular Neurosciences, Center for Brain Research, Medical University of Vienna, Vienna, Austria
    15. 15Research Group of Experimental Neuroanatomy and Developmental Biology, Hungarian Academy of Sciences & Department of Anatomy, Semmelweis University, Budapest, Hungary
    1. * Corresponding author. Tel: +36 1 2156 920 53609; E‐mail: alpar.alan{at}med.semmelweis-univ.hu

      Corresponding author. Tel: +46 8 524 87656; Fax: +46 8 341 960; E‐mail: Tibor.Harkany{at}ki.se

    1. These authors contributed equally to this study

    2. These authors share senior authorship

    Bodily responses to acute stress are orchestrated by the hierarchical release of stress hormones along the hypothalamic‐pituitary‐adrenal axis. Corticotropin‐releasing hormone (CRH)‐secreting neurons in the paraventricular nucleus of the hypothalamus are first order neurons in this axis, priming subsequent hormonal cascades upon CRH release into the portal circulation at the median eminence.

    Synopsis

    Bodily responses to acute stress are orchestrated by the hierarchical release of stress hormones along the hypothalamic‐pituitary‐adrenal axis. Corticotropin‐releasing hormone (CRH)‐secreting neurons in the paraventricular nucleus of the hypothalamus are first order neurons in this axis, priming subsequent hormonal cascades upon CRH release into the portal circulation at the median eminence.

    • Secretagogin is identified as the first neuronal Ca2+ sensor localized to parvocellular systems.

    • The transcriptome landscape of a novel hypothalamic neuron subtype, which contains secretagogin as Ca2+ sensor, is shown.

    • Secretagogin's Ca2+‐dependent protein interactome minimally required for regulated CRH release is defined.

    • Secretagogin is recognized to rate‐limit CRH release, thus limiting hormonal responses to stress.

    • acute stress
    • Ca2+ sensor
    • HPA axis
    • vesicular release
    • Received May 14, 2014.
    • Revision received October 7, 2014.
    • Accepted October 21, 2014.
    Roman A Romanov, Alán Alpár, Ming‐Dong Zhang, Amit Zeisel, André Calas, Marc Landry, Matthew Fuszard, Sally L Shirran, Robert Schnell, Árpád Dobolyi, Márk Oláh, Lauren Spence, Jan Mulder, Henrik Martens, Miklós Palkovits, Mathias Uhlen, Harald H Sitte, Catherine H Botting, Ludwig Wagner, Sten Linnarsson, Tomas Hökfelt, Tibor Harkany
  • Arhgef7 promotes activation of the Hippo pathway core kinase Lats
    1. Emad Heidary Arash1,
    2. Ki Myung Song1,
    3. Siyuan Song1,
    4. Ahmed Shiban1 and
    5. Liliana Attisano*,1
    1. 1Department of Biochemistry and Donnelly Centre, University of Toronto, Toronto, ON, Canada
    1. *Corresponding author. Tel: +1 416 946 3129; E‐mail: liliana.attisano{at}utoronto.ca

    βPix (Arhgef7) is required for cytoplasmic accumulation of Yap/Taz induced by either high cell density or cytoskeletal remodelling and acts by scaffolding the hippo kinase component Lats to Yap/Taz.

    Synopsis

    βPix (Arhgef7) is required for cytoplasmic accumulation of Yap/Taz induced by either high cell density or cytoskeletal remodelling and acts by scaffolding the hippo kinase component Lats to Yap/Taz.

    • Hippo pathway activation induces phosphorylation and cytoplasmic localization of the transcriptional regulators Yap/Taz.

    • βPix promotes Yap/Taz cytoplasmic localization and phosphorylation.

    • βPix scaffolds Lats to Yap/Taz to facilitate Yap/Taz phosphorylation.

    • βPix overexpression attenuates proliferation and migration of breast cancer cells.

    • Hippo
    • Arhgef7
    • Lats
    • mechanotransduction
    • Yap/Taz
    • Received October 3, 2014.
    • Revision received October 17, 2014.
    • Accepted October 28, 2014.
    Emad Heidary Arash, Ki Myung Song, Siyuan Song, Ahmed Shiban, Liliana Attisano
  • Escaping the endoplasmic reticulum: why does a molecular chaperone leave home for greener pastures?
    1. Teresa M Buck1 and
    2. Jeffrey L Brodsky (jbrodsky{at}pitt.edu) 1
    1. 1Department of Biological Sciences, University of Pittsburgh, Pittsburgh, PA, USA

    Molecular chaperones reside in nearly every organelle within a eukaryotic cell, and in each of these compartments, they ensure that protein homeostasis (or proteostasis) is maintained. In this issue, Wiseman and colleagues find that an ER lumenal chaperone escapes this compartment when a specific stress pathway is activated. The chaperone, an Hsp40 homolog known as ERdj3, transits through the secretory pathway to the extracellular space. During this journey, ERdj3 can escort an aggregation‐prone protein or it can identify aggregation‐prone proteins extracellularly, thereby functioning outside of its normal environment.

    See also: JC Genereux et al

    Selective secretion of an ER‐resident chaperone upon activation of the unfolded protein response contributes to extracellular proteostasis.

    Teresa M Buck, Jeffrey L Brodsky
  • A dysregulated acetyl/SUMO switch of FXR promotes hepatic inflammation in obesity
    1. Dong‐Hyun Kim1,
    2. Zhen Xiao2,
    3. Sanghoon Kwon1,
    4. Xiaoxiao Sun3,
    5. Daniel Ryerson1,
    6. David Tkac1,
    7. Ping Ma3,
    8. Shwu‐Yuan Wu4,
    9. Cheng‐Ming Chiang4,
    10. Edward Zhou5,
    11. H Eric Xu5,
    12. Jorma J Palvimo6,
    13. Lin‐Feng Chen7,
    14. Byron Kemper1 and
    15. Jongsook Kim Kemper*,1
    1. 1Department of Molecular and Integrative Physiology, University of Illinois at Urbana‐Champaign, Urbana, IL, USA
    2. 2Laboratory of Proteomics and Analytical Technologies, Advanced Technology Program, SAIC‐Frederick, Inc. National Cancer Institute‐Frederick, Frederick, MD, USA
    3. 3Department of Statistics, University of Georgia, Athens, GA, USA
    4. 4Simmons Comprehensive Cancer Center, Departments of Biochemistry and Pharmacology, University of Texas, Southwestern Medical Center, Dallas, TX, USA
    5. 5Laboratory of Structure Sciences, Van Andel Research Institute, Grand Rapids, MI, USA
    6. 6Institute of Biomedicine, University of Eastern Finland, Kuopio, Finland
    7. 7Department of Biochemistry, University of Illinois, Urbana, IL, USA
    1. *Corresponding author. Tel: +1 217 333 6317; Fax: +1 217 333 1133; E‐mail: jongsook{at}illinois.edu

    Elevated acetylation of the mouse nuclear Farnesoid X receptor (FXR) in obesity inhibits its SUMOylation, which promotes hepatic inflammation and metabolic dysfunction in vivo.

    Synopsis

    Acetylation levels of many transcriptional regulators are aberrantly elevated in obesity but the functional consequences are unclear. Elevated acetylation of the mouse nuclear Farnesoid X receptor (FXR) in obesity is found to inhibit its SUMOylation, constituting a molecular switch that promotes hepatic inflammation and metabolic dysfunction in vivo.

    • Agonist‐activated FXR is SUMO2‐modified at lysine 277 by the PIASy SUMO E3 ligase.

    • FXR SUMOylation inhibits inflammatory gene expression upon inflammatory signaling.

    • Selective inflammatory gene trans‐repression results from increased NF‐κB and decreased RXRα interaction of SUMO2‐FXR.

    • In obese mice, FXR acetylation at lysine 217 inhibits its SUMOylation and diminishes SUMO2‐dependent FXR anti‐inflammatory action.

    • acetylation
    • NF‐κB
    • PIASy
    • steatosis
    • SUMO2
    • Received July 15, 2014.
    • Revision received September 15, 2014.
    • Accepted October 8, 2014.
    Dong‐Hyun Kim, Zhen Xiao, Sanghoon Kwon, Xiaoxiao Sun, Daniel Ryerson, David Tkac, Ping Ma, Shwu‐Yuan Wu, Cheng‐Ming Chiang, Edward Zhou, H Eric Xu, Jorma J Palvimo, Lin‐Feng Chen, Byron Kemper, Jongsook Kim Kemper
  • Suppression of the HSF1‐mediated proteotoxic stress response by the metabolic stress sensor AMPK
    1. Siyuan Dai1,,
    2. Zijian Tang1,2,,
    3. Junyue Cao1,,
    4. Wei Zhou1,,
    5. Huawen Li1,
    6. Stephen Sampson1 and
    7. Chengkai Dai*,1
    1. 1 The Jackson Laboratory, Bar Harbor, ME, USA
    2. 2 Graduate Programs, Department of Molecular & Biomedical Sciences, The University of Maine, Orono, ME, USA
    1. *Corresponding author. Tel: +1 207 288 6927; Fax: +1 207 288 6078; E‐mail: Chengkai.Dai{at}jax.org
    1. These authors contributed equally to this work

    Identification of AMPK‐mediated HSF1 suppression by metabolic stress not only showcases a complex interplay of cellular stress responses, but also suggests a novel strategy to target HSF1 and proteostasis in malignancy.

    Synopsis

    HSF1 is the master regulator of the proteotoxic stress response, an evolutionarily conserved cytoprotective mechanism that critically preserves cellular proteostasis and facilitates oncogenesis. Identification of AMPK‐mediated HSF1 suppression by metabolic stress not only showcases a complex, interwoven network of cellular stress responses, but also pinpoints a novel strategy to target HSF1 and proteostasis in malignancy.

    • Metformin suppresses HSF1 and the HSF1‐mediated proteotoxic stress response through AMPK.

    • Upon activation, AMPK physically interacts with and phosphorylates HSF1 at Ser121.

    • Both leucine and glucose deprivation can repress the HSF1‐mediated proteotoxic stress response through AMPK.

    • Proteotoxic stress suppresses AMPK to increase HSF1 activation.

    • Metformin disrupts proteostasis in tumor cells through HSF1 inactivation, thereby retarding in vivo melanoma growth.

    • AMPK
    • HSF1
    • metformin
    • proteostasis
    • tumorigenesis
    • Received May 21, 2014.
    • Revision received October 6, 2014.
    • Accepted November 3, 2014.

    This is an open access article under the terms of the Creative Commons Attribution‐NonCommercial‐NoDerivs 4.0 License, which permits use and distribution in any medium, provided the original work is properly cited, the use is non‐commercial and no modifications or adaptations are made.

    Siyuan Dai, Zijian Tang, Junyue Cao, Wei Zhou, Huawen Li, Stephen Sampson, Chengkai Dai
  • Cytosolic RNA:DNA hybrids activate the cGAS–STING axis
    1. Arun K Mankan1,
    2. Tobias Schmidt1,,
    3. Dhruv Chauhan1,,
    4. Marion Goldeck2,
    5. Klara Höning1,
    6. Moritz Gaidt1,
    7. Andrew V Kubarenko14,
    8. Liudmila Andreeva3,
    9. Karl‐Peter Hopfner3 and
    10. Veit Hornung*,1
    1. 1Institute of Molecular Medicine, University Hospital University of Bonn, Bonn, Germany
    2. 2Institute of Clinical Chemistry and Clinical Pharmacology, University Hospital University of Bonn, Bonn, Germany
    3. 3Department of Biochemistry and Gene Center, Ludwig‐Maximilians‐University, Munich, Germany
    4. 4Institute of Clinical Chemistry and Clinical Pharmacology, University Hospital University of Bonn, Bonn, Germany
    1. *Corresponding author. Tel: +49 228 287 51203; Fax: +49 228 287 51201; E‐mail: veit.hornung{at}uni-bonn.de
    1. These authors contributed equally

    RNA:DNA hybrids are a novel class of intracellular PAMP molecules that can directly stimulate cGAS to produce cGAMP leading to the induction of antiviral response genes.

    Synopsis

    Next to dsDNA, cGAS can bind to cytoplasmic RNA:DNA hybrids. This results in the formation of cGAMP, which subsequently binds to and activates STING, leading to antiviral gene expression.

    • Cytosolic delivery of RNA:DNA hybrids triggers antiviral gene expression in myeloid cells.

    • RNA:DNA hybrid recognition depends on the cGAS–STING axis.

    • Hybrids directly bind to cGAS, resulting in its enzymatic activity.

    • cGAS
    • innate immunity
    • pattern recognition receptor
    • RNA:DNA hybrids
    • STING
    • Received April 14, 2014.
    • Revision received October 14, 2014.
    • Accepted October 24, 2014.
    Arun K Mankan, Tobias Schmidt, Dhruv Chauhan, Marion Goldeck, Klara Höning, Moritz Gaidt, Andrew V Kubarenko, Liudmila Andreeva, Karl‐Peter Hopfner, Veit Hornung
  • Orphan enzyme cuts down on sugar
    1. Siniša Urban (surban{at}jhmi.edu) 1
    1. 1Howard Hughes Medical Institute, Department of Molecular Biology & Genetics, Johns Hopkins University School of Medicine, Baltimore, MD, USA

    The reclusive enzymes that catalyze proteolysis inside the cell membrane are among the most widespread in nature, yet most remain ‘orphans’ whose cellular functions are poorly understood. Now, Voss et al identify Golgi‐resident glycosyltransferases and glycosidases as substrates for the presenilin‐like protease SPPL3. Shedding of these glycan‐modifying enzymes from the membrane down‐regulates global protein N‐glycosylation.

    See also: M Voss et al

    The presenilin‐like protease SPPL3 cleaves Golgi‐resident glycosyltransferases and glycosidases to regulate global protein N‐glycosylation.

    Siniša Urban