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  • Article
    Mitochondria are required for pro‐ageing features of the senescent phenotype
    Mitochondria are required for pro‐ageing features of the senescent phenotype
    1. Clara Correia‐Melo1,2,
    2. Francisco DM Marques1,
    3. Rhys Anderson1,
    4. Graeme Hewitt1,
    5. Rachael Hewitt3,
    6. John Cole3,
    7. Bernadette M Carroll1,
    8. Satomi Miwa1,
    9. Jodie Birch1,
    10. Alina Merz1,
    11. Michael D Rushton1,
    12. Michelle Charles1,
    13. Diana Jurk1,
    14. Stephen WG Tait3,
    15. Rafal Czapiewski1,
    16. Laura Greaves4,
    17. Glyn Nelson1,
    18. Mohammad Bohlooly‐Y5,
    19. Sergio Rodriguez‐Cuenca6,
    20. Antonio Vidal‐Puig6,
    21. Derek Mann7,
    22. Gabriele Saretzki1,
    23. Giovanni Quarato8,
    24. Douglas R Green8,
    25. Peter D Adams3,
    26. Thomas von Zglinicki1,
    27. Viktor I Korolchuk1 and
    28. João F Passos*,1
    1. 1Institute for Cell and Molecular Biosciences, Campus for Ageing and Vitality, Newcastle University Institute for Ageing, Newcastle University, Newcastle upon Tyne, UK
    2. 2GABBA Program, Abel Salazar Biomedical Sciences Institute University of Porto, Porto, Portugal
    3. 3Institute of Cancer Sciences, CR‐UK Beatson Institute, University of Glasgow, Glasgow, UK
    4. 4Wellcome Trust Centre for Mitochondrial Research, Newcastle University Centre for Brain Ageing and Vitality, Newcastle University, Newcastle upon Tyne, UK
    5. 5Transgenic RAD, Discovery Sciences, AstraZeneca, Mölndal, Sweden
    6. 6Metabolic Research Laboratories, Wellcome Trust‐MRC Institute of Metabolic Science, Addenbrooke's Hospital, University of Cambridge, Cambridge, UK
    7. 7Faculty of Medical Sciences, Institute of Cellular Medicine, Newcastle University, Newcastle upon Tyne, UK
    8. 8Department of Immunology, St. Jude Children's Research Hospital, Memphis, TN, USA
    1. *Corresponding author. Tel: +44 191 248 1222; Fax: +44 191 248 1101; E‐mail: joao.passos{at}ncl.ac.uk

    Cellular senescence serves as an important anticancer growth arrest mechanism, but also contributes to ageing. This study shows that mitochondria are necessary for the pro‐inflammatory phenotype during senescence and that senescence can be induced by mitochondrial biogenesis.

    Synopsis

    Cellular senescence serves as an important anticancer growth arrest mechanism, but also contributes to ageing. This study shows that mitochondria are necessary for the pro‐inflammatory phenotype during senescence and that senescence can be induced by mitochondrial biogenesis.

    • Mitochondria are required for the development of the pro‐oxidant and pro‐inflammatory features of senescence.

    • ATM, Akt, mTOR and PGC‐1β‐mediated mitochondrial biogenesis are involved in a novel senescence signalling pathway.

    • Mitochondrial biogenesis stabilizes senescence via a positive feedback loop involving ROS and the DDR.

    • ageing
    • inflammation
    • mitochondria
    • mTOR
    • senescence
    • Received August 19, 2015.
    • Revision received January 9, 2016.
    • Accepted January 12, 2016.

    This is an open access article under the terms of the Creative Commons Attribution 4.0 License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.

    Clara Correia‐Melo, Francisco DM Marques, Rhys Anderson, Graeme Hewitt, Rachael Hewitt, John Cole, Bernadette M Carroll, Satomi Miwa, Jodie Birch, Alina Merz, Michael D Rushton, Michelle Charles, Diana Jurk, Stephen WG Tait, Rafal Czapiewski, Laura Greaves, Glyn Nelson, Mohammad Bohlooly‐Y, Sergio Rodriguez‐Cuenca, Antonio Vidal‐Puig, Derek Mann, Gabriele Saretzki, Giovanni Quarato, Douglas R Green, Peter D Adams, Thomas von Zglinicki, Viktor I Korolchuk, João F Passos
  • Article
    p38γ and p38δ reprogram liver metabolism by modulating neutrophil infiltration
    p38γ and p38δ reprogram liver metabolism by modulating neutrophil infiltration
    1. Bárbara González‐Terán1,,
    2. Nuria Matesanz1,,
    3. Ivana Nikolic1,,
    4. María Angeles Verdugo1,2,
    5. Vinatha Sreeramkumar1,
    6. Lourdes Hernández‐Cosido3,4,
    7. Alfonso Mora1,
    8. Georgiana Crainiciuc1,
    9. María Laura Sáiz1,
    10. Edgar Bernardo1,
    11. Luis Leiva‐Vega1,
    12. Elena Rodríguez1,
    13. Victor Bondía1,
    14. Jorge L Torres5,6,
    15. Sonia Perez‐Sieira7,8,
    16. Luis Ortega3,4,
    17. Ana Cuenda2,
    18. Francisco Sanchez‐Madrid1,
    19. Rubén Nogueiras7,8,
    20. Andrés Hidalgo1,
    21. Miguel Marcos5,6 and
    22. Guadalupe Sabio*,1
    1. 1Fundación Centro Nacional de Investigaciones Cardiovasculares Carlos III, Madrid, Spain
    2. 2Department of Immunology and Oncology, Centro Nacional de Biotecnología/CSIC, Madrid, Spain
    3. 3Bariatric Surgery Unit, Department of General Surgery, University Hospital of Salamanca, Salamanca, Spain
    4. 4Department of Surgery, University of Salamanca, Salamanca, Spain
    5. 5Department of Internal Medicine, University Hospital of Salamanca‐IBSAL, Salamanca, Spain
    6. 6Department of Medicine, University of Salamanca, Salamanca, Spain
    7. 7Department of Physiology, CIMUS, University of Santiago de Compostela‐Instituto de Investigación Sanitaria, Santiago de Compostela, Spain
    8. 8CIBER Fisiopatología de la Obesidad y Nutrición (CIBERobn), Santiago de Compostela, Spain
    1. *Corresponding author. Tel: +34 91453 12 00; E‐mail: guadalupe.sabio{at}cnic.es
    1. These authors contributed equally to this work

    Mice lacking p38γ/δ in myeloid cells are protected against diet‐induced fatty liver. This effect is due to defective migration of p38γ/δ‐deficient neutrophils to the damaged liver, where they normally induce inflammation and metabolic changes.

    Synopsis

    Mice lacking p38γ/δ in myeloid cells are protected against diet‐induced fatty liver. This effect is due to defective migration of p38γ/δ‐deficient neutrophils to the damaged liver, where they normally induce inflammation and metabolic changes.

    • Expression of p38δ and p38γ is elevated in the liver from patients with non‐alcoholic fatty liver disease (NAFLD).

    • p38γ/δ KO and myeloid‐specific p38γ/δ cKO mice are resistant to hepatic steatosis induced by high‐fat diet or methionine‐choline‐deficient diet.

    • p38γ/δ control neutrophil migration to the damaged liver.

    • Migration of neutrophils to the liver is necessary for the development of steatosis.

    • diabetes
    • inflammation
    • obesity
    • steatosis
    • stress kinases
    • Received April 20, 2015.
    • Revision received December 18, 2015.
    • Accepted December 22, 2015.
    Bárbara González‐Terán, Nuria Matesanz, Ivana Nikolic, María Angeles Verdugo, Vinatha Sreeramkumar, Lourdes Hernández‐Cosido, Alfonso Mora, Georgiana Crainiciuc, María Laura Sáiz, Edgar Bernardo, Luis Leiva‐Vega, Elena Rodríguez, Victor Bondía, Jorge L Torres, Sonia Perez‐Sieira, Luis Ortega, Ana Cuenda, Francisco Sanchez‐Madrid, Rubén Nogueiras, Andrés Hidalgo, Miguel Marcos, Guadalupe Sabio
  • Article
    PAQR3 controls autophagy by integrating AMPK signaling to enhance ATG14L‐associated PI3K activity
    PAQR3 controls autophagy by integrating AMPK signaling to enhance ATG14L‐associated PI3K activity
    1. Da‐Qian Xu1,
    2. Zheng Wang1,
    3. Chen‐Yao Wang1,
    4. De‐Yi Zhang1,
    5. Hui‐Da Wan2,
    6. Zi‐Long Zhao1,
    7. Jin Gu1,
    8. Yong‐Xian Zhang1,
    9. Zhi‐Gang Li1,
    10. Kai‐Yang Man1,3,
    11. Yi Pan1,
    12. Zhi‐Fei Wang4,
    13. Zun‐Ji Ke4,
    14. Zhi‐Xue Liu1,
    15. Lu‐Jian Liao2 and
    16. Yan Chen*,1,3
    1. 1Key Laboratory of Nutrition and Metabolism, Institute for Nutritional Sciences, Shanghai Institutes for Biological Sciences, Graduate School of the Chinese Academy of Sciences, Chinese Academy of Sciences, Shanghai, China
    2. 2Shanghai Key Laboratory of Regulatory Biology, School of Life Sciences, East China Normal University, Shanghai, China
    3. 3School of Life Sciences and Technology, Shanghai Tech University, Shanghai, China
    4. 4School of Basic Medicine, Shanghai University of Traditional Chinese Medicine, Shanghai, China
    1. *Corresponding author. Tel: +86 21 54920916; E‐mail: ychen3{at}sibs.ac.cn

    Golgi‐resident protein PAQR3 facilitates formation of the autophagy‐initiating ATG14L–VPS34 complex. Upon glucose starvation, AMPK phosphorylates PAQR3 to enhance this function, thus integrating nutrient sensing with VPS34 activity.

    Synopsis

    Golgi‐resident protein PAQR3 facilitates formation of the autophagy‐initiating ATG14L–VPS34 complex. Upon glucose starvation, AMPK phosphorylates PAQR3 to enhance this function, thus integrating nutrient sensing with VPS34 activity.

    • PAQR3 enhances autophagosome formation and ATG14L‐linked class III PI3K activity without altering AMPK or mTOR activity.

    • PAQR3 facilitates the formation of the ATG14L‐linked VPS34 complex, but not the UVRAG‐associated VPS34 complex.

    • PAQR3 T32 is phosphorylated by AMPK upon glucose starvation in an ATG14L‐dependent manner.

    • PAQR3 T32 phosphorylation is required for ATG14L‐linked class III PI3K activation and autophagy initiation upon glucose starvation.

    • PAQR3‐deleted mice display deficiencies in exercise‐induced autophagy as well as behavioral disorders.

    • AMPK
    • autophagy
    • class III PI3K
    • glucose starvation
    • PAQR3
    • Received August 18, 2015.
    • Revision received December 24, 2015.
    • Accepted January 4, 2016.

    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.

    Da‐Qian Xu, Zheng Wang, Chen‐Yao Wang, De‐Yi Zhang, Hui‐Da Wan, Zi‐Long Zhao, Jin Gu, Yong‐Xian Zhang, Zhi‐Gang Li, Kai‐Yang Man, Yi Pan, Zhi‐Fei Wang, Zun‐Ji Ke, Zhi‐Xue Liu, Lu‐Jian Liao, Yan Chen
  • Article
    TFEB and TFE3 are novel components of the integrated stress response
    TFEB and TFE3 are novel components of the integrated stress response
    1. José A Martina1,
    2. Heba I Diab1,
    3. Owen A Brady1 and
    4. Rosa Puertollano*,1
    1. 1Cell Biology and Physiology Center, National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, MD, USA
    1. *Corresponding author. Tel: +1 301 451 2361; Fax: +1 301 402 1519; E‐mail: puertolr{at}mail.nih.gov

    The transcription factors TFEB and TFE3 are activated upon starvation‐induced mTORC1 inhibition, but also respond to ER stress in a PERK‐dependent manner. This finding reveals a hitherto unknown level of crosstalk between cellular stress pathways.

    Synopsis

    The transcription factors TFEB and TFE3 are activated upon starvation‐induced mTORC1 inhibition, but also respond to ER stress in a PERK‐dependent manner. This finding reveals a hitherto unknown level of crosstalk between cellular stress pathways.

    • ER stress activates TFEB and TFE3 through a process that requires PERK but not mTORC1.

    • TFEB and TFE3 modulate the Integrative Stress Response by regulating ATF4 expression both under ER stress and starvation conditions.

    • In response to stress TFE3 regulates not only autophagic and lysosomal genes, but also genes implicated in cellular homeostasis, stress response, signaling, and regulation of apoptosis.

    • TFEB and TFE3 play a dual role in cell fate by promoting either survival or cell death depending on the duration and strength of the stress.

    • ATF4
    • ER stress
    • PERK
    • TFE3
    • TFEB
    • Received November 3, 2015.
    • Revision received December 7, 2015.
    • Accepted December 10, 2015.
    José A Martina, Heba I Diab, Owen A Brady, Rosa Puertollano
  • Article
    Inducible chromatin priming is associated with the establishment of immunological memory in T cells
    Inducible chromatin priming is associated with the establishment of immunological memory in T cells
    1. Sarah L Bevington1,
    2. Pierre Cauchy1,
    3. Jason Piper2,
    4. Elisabeth Bertrand3,
    5. Naveen Lalli2,
    6. Rebecca C Jarvis1,
    7. Liam Niall Gilding1,
    8. Sascha Ott2,
    9. Constanze Bonifer1 and
    10. Peter N Cockerill*,1
    1. 1Institute of Biomedical Research, College of Medicine and Dentistry, University of Birmingham, Birmingham, UK
    2. 2Warwick Systems Biology Centre, University of Warwick, Coventry, UK
    3. 3Section of Experimental Haematology, Leeds Institute for Molecular Medicine, University of Leeds, Leeds, UK
    1. *Corresponding author. Tel: +44 121 4146841; E‐mail: p.n.cockerill{at}bham.ac.uk

    Naïve T cells become epigenetically imprinted when activated and stably maintain regions of accessible active chromatin to support efficient reactivation of genes in primed T cells.

    Synopsis

    Naïve T cells become epigenetically imprinted when activated and subsequently they stably maintain regions of accessible active chromatin bound by ETS1 and RUNX1. These primed DNA elements support efficient reactivation of inducible genes in previously activated T cells.

    • Naïve T cells acquire a specific epigenetic imprint after initial T‐cell activation.

    • Primed T cells and memory‐phenotype cells retain a subset of accessible chromatin sites as DNase I‐hypersensitive sites.

    • ETS‐1 and RUNX1 remain bound to primed DNase I‐hypersensitive sites in previously activated T cells.

    • Primed DNase I‐hypersensitive sites facilitate inducible enhancer function.

    • chromatin
    • epigenetics
    • gene regulation
    • immunity
    • memory T cell
    • Received July 13, 2015.
    • Revision received December 18, 2015.
    • Accepted December 22, 2015.

    This is an open access article under the terms of the Creative Commons Attribution 4.0 License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.

    Sarah L Bevington, Pierre Cauchy, Jason Piper, Elisabeth Bertrand, Naveen Lalli, Rebecca C Jarvis, Liam Niall Gilding, Sascha Ott, Constanze Bonifer, Peter N Cockerill
  • Review
    Touch, act and go: landing and operating on nucleosomes
    Touch, act and go: landing and operating on nucleosomes
    1. Valentina Speranzini1,
    2. Simona Pilotto1,
    3. Titia K Sixma2 and
    4. Andrea Mattevi*,1
    1. 1Department of Biology and Biotechnology, University of Pavia, Pavia, Italy
    2. 2Division of Biochemistry and Cancer Genomics Center, Netherlands Cancer Institute, Amsterdam, The Netherlands
    1. *Corresponding author. Tel: +39032985525; E‐mail: andrea.mattevi{at}unipv.it

    This review summarizes the emerging structural understanding of nucleosome recognition by multiprotein readers, writers and erasers of chromatin marks, which are key for integrating information from both DNA and histone modifications.

    • chromatin
    • epigenetics
    • molecular recognition
    • nucleosome
    • structural biology
    • Received October 30, 2015.
    • Revision received November 30, 2015.
    • Accepted December 10, 2015.
    Valentina Speranzini, Simona Pilotto, Titia K Sixma, Andrea Mattevi
  • Article
    Identification and function of conformational dynamics in the multidomain GTPase dynamin
    Identification and function of conformational dynamics in the multidomain GTPase dynamin
    1. Saipraveen Srinivasan1,
    2. Venkatasubramanian Dharmarajan2,
    3. Dana Kim Reed1,
    4. Patrick R Griffin2 and
    5. Sandra L Schmid*,1
    1. 1Department of Cell Biology, UT Southwestern Medical Center, Dallas, TX, USA
    2. 2Department of Molecular Therapeutics, The Scripps Research Institute, Jupiter, FL, USA
    1. *Corresponding author. Tel: +1 214 648 3948; E‐mail: sandra.schmid{at}utsouthwestern.edu

    Dynamin‐catalyzed membrane fission requires long‐range nucleotide and/or membrane binding‐induced conformational changes and domain rearrangements that are identified and functionally characterized in this study.

    Synopsis

    Dynamin‐catalyzed membrane fission requires long‐range nucleotide and/or membrane binding‐induced conformational changes and domain rearrangements that are identified and functionally characterized in this study.

    • Ligand‐induced conformational changes in dynamin were identified by HDX‐MS.

    • An allosteric relay helix, α2S, transmits conformational information from the G domain to the membrane and vice versa.

    • FRET analyses reveal conformational switches of the PH domain.

    • When locked in a closed conformation, the PH domain acts in an auto‐inhibitory fashion to regulate membrane binding and assembly.

    • The PH domain conformational switch is impaired in the centronuclear myopathy‐causing mutant Dyn2S619L.

    • centronuclear myopathy
    • clathrin‐mediated endocytosis
    • hydrogen–deuterium exchange
    • membrane fission
    • pleckstrin homology domain
    • Received November 11, 2015.
    • Revision received December 9, 2015.
    • Accepted December 11, 2015.
    Saipraveen Srinivasan, Venkatasubramanian Dharmarajan, Dana Kim Reed, Patrick R Griffin, Sandra L Schmid