Metabolism
- ER–endosome contact sites: molecular compositions and functions
- 1Centre for Cancer Biomedicine, Faculty of Medicine, University of Oslo, Oslo, Norway
- 2Department of Molecular Cell Biology, Institute for Cancer Research Oslo University Hospital, Oslo, Norway
- 3Centre of Molecular Inflammation Research, Faculty of Medicine, Norwegian University of Science and Technology, Trondheim, Norway
- ↵*Corresponding author. Tel: +47 22781818; Fax +47 22781845; E‐mail: stenmark{at}ulrik.uio.no
Membrane contact sites, defined as sites of close apposition between two membranes, are crucial for the direct exchange of information between distinct endomembrane compartments. This review highlights the diverse functions of ER‐endosome contact sites.
The EMBO Journal (2015) 34: 1848–1858
- Received March 10, 2015.
- Revision received March 30, 2015.
- Accepted March 31, 2015.
- © 2015 The Authors
- Reciprocal regulation of amino acid import and epigenetic state through Lat1 and EZH2
- Stephen G Dann*,1,
- Michael Ryskin2,
- Anthony M Barsotti2,
- Jonathon Golas2,
- Celine Shi2,
- Miriam Miranda2,
- Christine Hosselet2,
- Luanna Lemon2,
- Judy Lucas2,
- Maha Karnoub3,
- Fang Wang2,
- Jeremy S Myers2,
- Scott J Garza1,
- Maximillian T Follettie2,
- Kenneth G Geles2,
- Anke Klippel3,
- Robert A Rollins2 and
- Valeria R Fantin1
- 1Pfizer Oncology Research Unit, San Diego, CA, USA
- 2Pfizer Oncology Research Unit, Pearl River, NY, USA
- 3Celgene, Summit, NJ, USA
- ↵*Corresponding author. Tel: +1 845 602 2370; Fax: +1 845 602 5557; E‐mail: stephen.dann{at}pfizer.com
The amino acid transporter Lat1 increases cellular S‐adenosylmethionine concentrations and thereby EZH2 activity, and this dictates the differentiation state of cancer cells and tumour growth.
Synopsis
A metabolic–epigenetic feedback loop between the methionine transporter Lat1 and the histone methyltransferase EZH2 dictates differentiation state in a malignant context.
Cells sorted for high CD98/Lat1 expression contain elevated methionine cycle metabolites and more active EZH2 and are more aggressive in lung cancer models.
Amino acid restriction, methionine dropout, or Lat1 shRNA impairs EZH2 activity due to reduction in cellular S‐adenosylmethionine.
Lat1 and EZH2 expressions correlate with a less‐differentiated state as illustrated by spheroid models of cancer cell differentiation, retinoic acid‐mediated transcription, and immunohistochemical analysis of human lung cancer.
EZH2 activity and PRC2 activity derepress Lat1 expression through direct promoter binding and subsequent transcriptional repression of RXRα.
The EMBO Journal (2015) 34: 1773–1785
- Received February 7, 2014.
- Revision received April 10, 2015.
- Accepted April 14, 2015.
- © 2015 The Authors
- A NAD‐dependent glutamate dehydrogenase coordinates metabolism with cell division in Caulobacter crescentus
- François Beaufay1,
- Jérôme Coppine1,
- Aurélie Mayard1,
- Géraldine Laloux2,
- Xavier De Bolle1 and
- Régis Hallez*,1
- 1Bacterial Cell Cycle & Development (BCcD), URBM, University of Namur, Namur, Belgium
- 2de Duve Institute, Université catholique de Louvain, Brussels, Belgium
- ↵*Corresponding author. Tel: +32 81 724 244; E‐mail: regis.hallez{at}unamur.be
GdhZ and KidO are complementary negative regulators of FtsZ that connect metabolic conditions to cell division in Caulobacter crescentus. GdhZ is an inhibitor of FtsZ polymerization while KidO prevents FtsZ filament bundling in response to nutrient availability.
Synopsis
GdhZ and KidO are metabolic regulators of cell division in Caulobacter crescentus. Once bound to their substrates, both proteins synergistically stimulate cytokinesis by triggering Z‐ring disassembly by two complementary mechanisms in late predivisional cells (G2).
Caulobacter crescentus modulates cell division according to its metabolic activity.
Catalytically active GdhZ stimulates GTPase activity of FtsZ.
KidO bound to NADH inhibits lateral interactions between FtsZ protofilaments.
KidO and GdhZ cooperate to disassemble the Z‐ring.
The EMBO Journal (2015) 34: 1786–1800
- Received December 5, 2014.
- Revision received April 14, 2015.
- Accepted April 21, 2015.
- © 2015 The Authors
- The transcription factor Cabut coordinates energy metabolism and the circadian clock in response to sugar sensing
- Osnat Bartok1,†,
- Mari Teesalu2,3,†,
- Reut Ashwall‐Fluss1,
- Varun Pandey1,
- Mor Hanan1,
- Bohdana M Rovenko2,3,
- Minna Poukkula3,
- Essi Havula2,3,
- Arieh Moussaieff4,5,
- Sadanand Vodala6,
- Yaakov Nahmias4,5,
- Sebastian Kadener*,1 and
- Ville Hietakangas*,2,3
- 1Biological Chemistry Department, Silberman Institute of Life Sciences The Hebrew University of Jerusalem, Jerusalem, Israel
- 2Department of Biosciences, University of Helsinki, Helsinki, Finland
- 3Institute of Biotechnology, University of Helsinki, Helsinki, Finland
- 4Department of Cell Biology, Silberman Institute of Life Sciences The Hebrew University of Jerusalem, Jerusalem, Israel
- 5Center for Bioengineering, The Hebrew University of Jerusalem, Jerusalem, Israel
- 6Howard Hughes Medical Institute, Brandeis University, Waltham, MA, USA
- ↵*
Corresponding author. Tel.: +358 2 94158001; E‐mail: ville.hietakangas{at}helsinki.fi
Corresponding author. Tel.: +972 2 6585099; E‐mail: skadener{at}mail.huji.ac.il
↵† These authors contributed equally to this work
Sugar feeding in flies induces specific gene expression but also triggers a repressive branch via transcription factor Cabut. Induction of Cabut alters accumulation of the metabolic enzyme PEPCK and provides a regulatory link between nutrient sensing and the circadian clock.
Synopsis
Sugar feeding in flies induces specific gene expression but also triggers a repressive branch via transcription factor Cabut. Induction of Cabut alters accumulation of the metabolic enzyme PEPCK and provides a regulatory link between nutrient sensing and the circadian clock.
Transcriptional regulator Cabut is directly activated by Mondo‐Mlx upon sugar feeding.
Cabut represses metabolic genes upon sugar feeding.
Cabut represses the expression of both isoforms of the phosphoenolpyruvate carboxykinase PEPCK.
Deregulation of PEPCK1 contributes to the metabolic imbalance and lethality of mlx mutant animals.
Cabut represses the cycling of metabolic target genes of the circadian clock.
The EMBO Journal (2015) 34: 1538–1553
- Received February 25, 2015.
- Revision received March 31, 2015.
- Accepted April 1, 2015.
- © 2015 The Authors
- Aerobic glycolysis tunes YAP/TAZ transcriptional activity
- Elena Enzo1,6,†,
- Giulia Santinon1,†,
- Arianna Pocaterra1,
- Mariaceleste Aragona1,
- Silvia Bresolin2,
- Mattia Forcato3,
- Daniela Grifoni4,
- Annalisa Pession4,
- Francesca Zanconato1,
- Giulia Guzzo5,
- Silvio Bicciato3 and
- Sirio Dupont*,1
- 1Department of Molecular Medicine, University of Padova, Padua, Italy
- 2Department of Woman and Child Health, University of Padova, Padua, Italy
- 3Department of Life Sciences, Center for Genome Research University of Modena and Reggio Emilia, Modena, Italy
- 4Department of Pharmacy and Biotechnologies, University of Bologna, Bologna, Italy
- 5Department of Biomedical Sciences, University of Padova, Padua, Italy
- 6Centre for Regenerative Medicine “Stefano Ferrari” University of Modena and Reggio Emilia, Modena, Italy
- ↵*Corresponding author. Tel: +39 049 827 6095; Fax: +39 049 827 6079; E‐mail: sirio.dupont{at}unipd.it
↵† These authors contributed equally to this work
The direct binding of Phosphofructokinase‐1 with TEAD transcription factors in breast cancer cells unravels a new molecular link between cancer cell metabolism and YAP/TAZ‐mediated gene regulation.
Synopsis
The direct binding of Phosphofructokinase‐1 with TEAD transcription factors in breast cancer cells unravels a new molecular link between cancer cell metabolism and YAP/TAZ‐mediated gene regulation.
YAP/TAZ transcriptional activity is regulated by glucose metabolism and glycolysis.
Glycolysis modulates YAP/TAZ interaction with TEAD transcription factors.
Glycolysis intersects YAP/TAZ activity to regulate cancer cell proliferation and tissue overgrowth.
The EMBO Journal (2015) 34: 1349–1370
- Received October 23, 2014.
- Revision received February 7, 2015.
- Accepted February 26, 2015.
- © 2015 The Authors
- SIRT3‐dependent GOT2 acetylation status affects the malate–aspartate NADH shuttle activity and pancreatic tumor growth
- Hui Yang1,†,
- Lisha Zhou1,†,
- Qian Shi1,
- Yuzheng Zhao2,
- Huaipeng Lin1,
- Mengli Zhang1,
- Shimin Zhao1,
- Yi Yang2,
- Zhi‐Qiang Ling3,
- Kun‐Liang Guan*,1,4,
- Yue Xiong*,1,5 and
- Dan Ye*,1
- 1State Key Laboratory of Genetic Engineering, Collaborative Innovation Center for Genetics and Development, School of Life Sciences, Molecular and Cell Biology Lab, Institutes of Biomedical Sciences Shanghai Medical College Fudan University, Shanghai, China
- 2School of Pharmacy East China University of Science and Technology, Shanghai, China
- 3Zhejiang Cancer Research Institute Zhejiang Province Cancer Hospital Zhejiang Cancer Center, Hangzhou, China
- 4Department of Pharmacology and Moores Cancer Center, University of California San Diego, La Jolla, CA, USA
- 5Lineberger Comprehensive Cancer Center, Department of Biochemistry and Biophysics, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA
- ↵*
Corresponding author. Tel: +1 8582461482; E‐mail: kuguan{at}ucsd.edu
Corresponding author. Tel: +1 9199622142; Fax: +1 9199668799; E‐mail: yxiong{at}email.unc.edu
Corresponding author. Tel: +86 2154237834; Fax: +86 2154237450; E‐mail: yedan{at}fudan.edu.cn
↵† These authors contributed equally to this work
Acetylation of oxaloacetate transaminase (GOT2) promotes its binding with malate dehydrogenase (MDH2), thereby regulating the malate–aspartate shuttle activity, cytosol‐to‐mitochondrion transfer of NADH, oxidative protection and tumor growth.
Synopsis
Acetylation of oxaloacetate transaminase (GOT2) promotes its binding with malate dehydrogenase (MDH2), thereby regulating the malate–aspartate shuttle activity, cytosol‐to‐mitochondrion transfer of NADH, oxidative protection and tumor growth.
GOT2 acetylation at three lysine residues enhances its association with MDH2.
SIRT3 is the major deacetylase of GOT2.
Acetylation of GOT2 modulates mitochondrial NADH/NAD+ redox status, energy production, and cell survival during oxidative stress.
GOT2 K159 acetylation is increased in human pancreatic tumors, correlating with reduced SIRT3 expression.
The EMBO Journal (2015) 34: 1110–1125
- Received January 19, 2015.
- Revision received February 2, 2015.
- Accepted February 4, 2015.
- © 2015 The Authors
- An LXR–NCOA5 gene regulatory complex directs inflammatory crosstalk‐dependent repression of macrophage cholesterol efflux
- Mark A Gillespie1,
- Elizabeth S Gold2,
- Stephen A Ramsey3,
- Irina Podolsky2,
- Alan Aderem2 and
- Jeffrey A Ranish*,1
- 1Institute for Systems Biology, Seattle, WA, USA
- 2Seattle Biomedical Research Institute, Seattle, WA, USA
- 3Department of Biomedical Sciences, Oregon State University, Corvallis, OR, USA
- ↵*Corresponding author. Tel: +1 206 732 1357; Fax: +1 206 732 1299; E‐mail: jeff.ranish{at}systemsbiology.org
Inflammatory signaling impinges on LXR–NCOA5 dependent mechanisms controlling lipid transporter expression and macrophage cholesterol efflux.
Synopsis
NCOA5 is a key target of the crosstalk between pro‐inflammatory TLR3 signaling and the anti‐inflammatory LXR pathway. Here, NCOA5 functions as an LXR corepressor to attenuate expression of the lipid transporter Abca1, thereby providing a mechanism whereby inflammatory signaling leads to repression of macrophage cholesterol efflux.
Promoter enrichment‐quantitative mass spectrometry (PE‐QMS) maps the dynamic assembly of protein complexes at the Abca1 promoter.
PE‐QMS identifies the LXR ligand‐stimulated and LXR binding‐induced occupancy of NCOA5 at the Abca1 promoter.
In response to TLR3‐LXR signal crosstalk, NCOA5 is recruited to the Abca1 promoter, where it functions as an LXR corepressor.
NCOA5 inhibits Abca1 gene expression by disrupting RNA Polymerase II recruitment and function.
The EMBO Journal (2015) 34: 1244–1258
- Received August 15, 2014.
- Revision received February 11, 2015.
- Accepted February 13, 2015.
- © 2015 The Authors
- Interrupting synoviolin play at the ER: a plausible action to elevate mitochondrial energetics and silence obesity
Obesity is a global concern, which has been linked to increased risk for cardiovascular disease, type 2 diabetes, atherosclerosis, non‐alcoholic fatty liver, and cancer. In this issue of The EMBO Journal, Fujita et al (2015) describe the role of an endoplasmic reticulum (ER)‐resident E3 ubiquitin ligase, synoviolin, and its ability to control body weight and energy expenditure by targeting PGC‐1β, a transcriptional modulator of mitochondrial oxidative metabolism.
See also: H Fujita et al (April 2015)
Inhibiting the E3 ligase synoviolin with the specific inhibitor LS‐102 can be potentially exploited to fight obesity, as this ligase is now shown to control body weight and energy expenditure in mice.
- © 2015 The Authors
- Toward beta cell replacement for diabetes
- 1The New York Stem Cell Foundation Research Institute, New York, NY, USA
- 2Naomi Berrie Diabetes Center & Department of Pediatrics, College of Physicians and Surgeons, Columbia University, New York, NY, USA
- 3Columbia Center for Translational Immunology, Department of Medicine and Naomi Berrie Diabetes Center, Columbia University, New York, NY, USA
- ↵*Corresponding author. Tel: +1 212 851 4890; E‐mail: de2220{at}cumc.columbia.edu
Dieter Egli & colleagues provide a stem cell perspective on pancreatic beta‐cells for diabetes therapies and disease modeling.
The EMBO Journal (2015) 34: 841–855
- Received November 27, 2014.
- Revision received January 13, 2015.
- Accepted January 22, 2015.
- © 2015 The Authors
- Metabolic remodeling: a pyruvate transport affair
Metabolic remodeling is a major determinant for many cell fate decisions, and a switch from respiration to aerobic glycolysis is generally considered as a hallmark of cancer cell transformation. Pyruvate is a key metabolite at the major junction of carbohydrate metabolism between cytosolic glycolysis and the mitochondrial Krebs cycle. In this issue of The EMBO Journal, Bender et al show that yeast cells regulate pyruvate uptake into mitochondria, and thus its metabolic fate, by expressing alternative pyruvate carrier complexes with different activities.
See also: T Bender et al (April 2015)
A new study in yeast links metabolic changes to the expression of alternative mitochondrial pyruvate carriers (MPCs) displaying different activities, adding to recent studies in cancer cells that associated MPC function to metabolic reprogramming and cell fate.
- © 2015 The Authors
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