Metabolism
- Lipophagy prevents activity‐dependent neurodegeneration due to dihydroceramide accumulation in vivo
- Wei‐Hung Jung1,†,
- Chung‐Chih Liu1,†,
- Yu‐Lian Yu1,
- Yu‐Chin Chang1,
- Wen‐Yu Lien1,
- Hsi‐Chun Chao2,
- Shu‐Yi Huang3,
- Ching‐Hua Kuo2,
- Han‐Chen Ho4 and
- Chih‐Chiang Chan (chancc1{at}ntu.edu.tw)*,1
- 1Graduate Institute of Physiology, College of Medicine, National Taiwan University, Taipei, Taiwan
- 2School of Pharmacy, College of Medicine, National Taiwan University, Taipei, Taiwan
- 3Department of Medical Research, National Taiwan University Hospital, Taipei, Taiwan
- 4Department of Anatomy, Tzu‐Chi University, Hualien, Taiwan
- ↵*Corresponding author. Tel: +886 223123456 88240; E‐mail chancc1{at}ntu.edu.tw
↵† These authors contributed equally to this work
This study dissects the role of the fly dhCer desaturase ifc in neurons by genetic and pharmaceutical methods. dhCer desaturase is required for neuronal maintenance in vivo and lipophagy activation prevents activity‐dependent degeneration due to dhCer accumulation.
Synopsis
This study dissects the role of the fly dhCer desaturase ifc in neurons by genetic and pharmaceutical methods. dhCer desaturase is required for neuronal maintenance in vivo and lipophagy activation prevents activity‐dependent degeneration due to dhCer accumulation.
Light stimulation leads to ROS increase and apoptotic cell death in ifc‐KO photoreceptors, resulting in activity‐dependent neurodegeneration.
Enhancing lipophagy reduces lipid droplet accumulation and rescues ifc‐KO defects, indicating that lipophagy plays a protective role.
Human dhCer desaturase rescues ifc‐KO larval lethality in Drosophila and rapamycin reverses defects caused by dhCer accumulation in human neuroblastoma cells, suggesting evolutionarily conserved functions.
- Received October 7, 2016.
- Revision received March 30, 2017.
- Accepted April 6, 2017.
- © 2017 The Authors
- Bacilli glutamate dehydrogenases diverged via coevolution of transcription and enzyme regulation
- Lianet Noda‐Garcia1,
- Maria Luisa Romero Romero1,
- Liam M Longo1,
- Ilana Kolodkin‐Gal2 and
- Dan S Tawfik (dan.tawfik{at}weizmann.ac.il)*,1
- 1Department of Biomolecular Sciences, Weizmann Institute of Science, Rehovot, Israel
- 2Department of Molecular Genetics, Weizmann Institute of Science, Rehovot, Israel
- ↵*Corresponding author. Tel: +972 8 934 3637; E‐mail: dan.tawfik{at}weizmann.ac.il
Bacilli have two glutamate dehydrogenase paralogues. Regulation has diverged from transcriptional control in one paralogue (RocG) to enzyme control in the other (GudB), thus creating incompatibility upon swaps of enzymes and regulatory regions.
Synopsis
Bacilli have two glutamate dehydrogenase paralogues. Regulation has diverged from transcriptional control in one paralogue (RocG) to enzyme control in the other (GudB), thus creating incompatibility upon swaps of enzymes and regulatory regions (promoter/terminator).
Swapping enzymes and regulatory regions of the Bacilli glutamate dehydrogenase paralogues reveals coevolution of transcription and enzyme regulation.
Coevolution of transcriptional and enzymatic regulation underlies paralogue‐specific spatio‐temporal control.
The Bacilli glutamate dehydrogenases are regulated via oligomer assembly.
- Received January 25, 2017.
- Revision received March 23, 2017.
- Accepted March 27, 2017.
- © 2017 The Authors
- The phosphorylation status of T522 modulates tissue‐specific functions of SIRT1 in energy metabolism in mice
- Jing Lu1,2,†,
- Qing Xu1,†,
- Ming Ji1,†,
- Xiumei Guo1,4,†,
- Xiaojiang Xu3,
- David C Fargo3 and
- Xiaoling Li (lix3{at}niehs.nih.gov)*,1
- 1Signal Transduction Laboratory, National Institute of Environmental Health Sciences, Research Triangle Park, NC, USA
- 2Department of Pathology, Wake Forest School of Medicine, Winston‐Salem, NC, USA
- 3Integrative Bioinformatics, National Institute of Environmental Health Sciences, Research Triangle Park, NC, USA
- 4Guangzhou DiagCor Clinical Laboratory Co., Ltd, Guangzhou, Guangdong, China
- ↵*Corresponding author. Tel: +1 919 541 9817; E‐mail: lix3{at}niehs.nih.gov
↵† These authors contributed equally to this work
The phosphorylation of SIRT1 T522 is a critical element in the tissue‐specific regulation of SIRT1 activity in mice. This finding unveils an important link between environmental cues, SIRT1 phosphorylation and energy homeostasis.
Synopsis
The phosphorylation of SIRT1 T522 is a critical element in the tissue‐specific regulation of SIRT1 activity in mice. This finding unveils an important link between environmental cues, SIRT1 phosphorylation and energy homeostasis.
SIRT1 is dephosphorylated at T522 during normal adipogenesis.
Knocking‐in a constitutive T522 phosphorylation mimic activates the β‐catenin/GATA3 pathway, repressing PPARγ signaling and adipogenesis in mice.
Hepatic SIRT1 is hyperphosphorylated at T522 upon high‐fat diet feeding.
Knocking‐in a SIRT1 mutant defective in T522 phosphorylation disrupts hepatic fatty acid oxidation, resulting in hepatic steatosis in mice on high‐fat diet.
EMBO Reports (2017) 18: 841–857
- Received December 13, 2016.
- Revision received February 21, 2017.
- Accepted February 22, 2017.
- Published 2017. This article is a U.S. Government work and is in the public domain in the USA
- CUE domain‐containing protein 2 promotes the Warburg effect and tumorigenesis
- Xiuying Zhong1,†,
- Shengya Tian1,†,
- Xiang Zhang1,
- Xinwei Diao2,
- Fangting Dong2,
- Jie Yang2,
- Zhaoyong Li1,
- Linchong Sun1,
- Lin Wang1,
- Xiaoping He1,
- Gongwei Wu1,
- Xin Hu1,
- Lihua Wang1,
- Libing Song3,
- Huafeng Zhang1,
- Xin Pan2,
- Ailing Li (liailing{at}hotmail.com)*,2 and
- Ping Gao (pgao2{at}ustc.edu.cn)*,1
- 1Hefei National Laboratory for Physical Sciences at Microscale, the CAS Key Laboratory of Innate Immunity and Chronic Disease, Innovation Center for Cell Signaling Network, School of Life Sciences, University of Science and Technology of China, Hefei, China
- 2Institute of Basic Medical Sciences, National Center of Biomedical Analysis, Beijing, China
- 3State Key Laboratory of Oncology in Southern China and Departments of Experimental Research, Sun Yat‐sen University Cancer Center, Guangzhou, China
- ↵*
Corresponding author. Tel: +86 10 66930344; E‐mail: liailing{at}hotmail.com
Corresponding author. Tel: +86 551 63607033; E‐mail: pgao2{at}ustc.edu.cn
↵† These authors contributed equally to this work
CUEDC2 has originally been described to promote proteasome function, but regulates also other cellular key events, including tumorigenesis. This study shows that CUEDC2 facilitates the Warburg effect in cancer cells by up‐regulating the glycolytic enzymes GLUT3 and LDHA.
Synopsis
CUEDC2 has originally been described to promote proteasome function, but regulates also other cellular key events, including tumorigenesis. This study shows that CUEDC2 facilitates the Warburg effect in cancer cells by up‐regulating the glycolytic enzymes GLUT3 and LDHA.
CUEDC2 facilitates the Warburg effect in cancer cells by regulating GLUT3 and LDHA.
CUEDC2 activates GLUT3 and LDHA by stabilizing the glucocorticoid receptor and 14‐3‐3ζ.
Enhanced aerobic glycolysis is essential for CUEDC2 to drive cancer progression.
Clinical HCC samples show aberrant expression of CUEDC2, GLUT3 and LDHA.
EMBO Reports (2017) 18: 809–825
- Received November 2, 2016.
- Revision received February 5, 2017.
- Accepted February 15, 2017.
- © 2017 The Authors
- TGFβ1‐induced leucine limitation uncovered by differential ribosome codon reading
- Fabricio Loayza‐Puch (f.loayza{at}nki.nl)*,1,†,
- Koos Rooijers1,†,
- Jelle Zijlstra1,
- Behzad Moumbeini1,
- Esther A Zaal2,
- Joachim F Oude Vrielink1,
- Rui Lopes1,
- Alejandro P Ugalde1,
- Celia R Berkers2 and
- Reuven Agami (r.agami{at}nki.nl)*,1,3
- 1Division of Biological Stress Response, The Netherlands Cancer Institute, Amsterdam, The Netherlands
- 2Biomolecular Mass Spectrometry and Proteomics, Bijvoet Center for Biomolecular Research, Utrecht University, Utrecht, The Netherlands
- 3Erasmus MC, Rotterdam University, Rotterdam, The Netherlands
- ↵*
Corresponding author. Tel: +31 205122048; E‐mail: f.loayza{at}nki.nl
Corresponding author. Tel: +31 205122079; E‐mail: r.agami{at}nki.nl
↵† These authors contributed equally to this work
TGFβ1 treatment of human breast epithelial cells reduces the expression of SLC3A2, a subunit of the leucine transporter, which diminishes leucine uptake and inhibits cell proliferation.
Synopsis
TGFβ1 treatment of human breast epithelial cells reduces the expression of SLC3A2, a subunit of the leucine transporter, which diminishes leucine uptake and inhibits cell proliferation.
TGFβ1 induces pausing of ribosomes at leucine codons in MCF10A cells.
MCF10A cells downregulate the leucine transporter SLC3A2 and reduce leucine uptake in response to TGFβ1.
Exogenous leucine releases the codon‐specific stalling induced by TGFβ1.
Reconstitution of the SLC3A2 transporter rescues the stalling of ribosomes at leucine codons as well as TGFβ1‐induced proliferation inhibition.
EMBO Reports (2017) 18: 549–557
- Received January 26, 2017.
- Revision received February 3, 2017.
- Accepted February 8, 2017.
- © 2017 The Authors
- Adipocyte SIRT1 controls systemic insulin sensitivity by modulating macrophages in adipose tissue
- Xiaoyan Hui1,2,
- Mingliang Zhang3,
- Ping Gu1,2,4,
- Kuai Li5,6,
- Yuan Gao1,2,
- Donghai Wu5,6,
- Yu Wang (yuwanghk{at}hku.hk)*,1,7 and
- Aimin Xu (amxu{at}hku.hk)*,1,2,7
- 1State Key Laboratory of Pharmaceutical Biotechnology, The University of Hong Kong, Hong Kong, China
- 2Department of Medicine, The University of Hong Kong, Hong Kong, China
- 3Department of Endocrinology and Metabolism, Shanghai Jiao Tong University Affiliated Sixth People's Hospital, Shanghai, China
- 4Department of Endocrinology, School of Medicine, Nanjing University Nanjing General Hospital of Nanjing Military Command, Nanjing, China
- 5CAS Key Laboratory of Regenerative Biology, Joint School of Life Sciences, Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences, Guangzhou, China
- 6CAS Key Laboratory of Regenerative Biology, Joint School of Life Sciences, Guangzhou Medical University, Guangzhou, China
- 7Department of Pharmacology and Pharmacy, The University of Hong Kong, Hong Kong, China
- ↵*
Corresponding author. Tel: +852 39176864; Fax: +852 28170859; E‐mail: yuwanghk{at}hku.hk
Corresponding author. Tel: +852 39179754; Fax: +852 28162095; E‐mail: amxu{at}hku.hk
The deacetylase SIRT1 protects against metabolic disorders in many tissues. SIRT1 also acts on the transcription factor NFATc1 in adipocytes, thereby enhancing IL‐4 expression. Sirt1 deletion lowers IL‐4 levels, reduces adipose‐resident M2 macrophages, and increases inflammation.
Synopsis
The deacetylase SIRT1 protects against metabolic disorders in many tissues. SIRT1 also acts on the transcription factor NFATc1 in adipocytes, thereby enhancing IL‐4 expression. Sirt1 deletion lowers IL‐4 levels, reduces adipose‐resident M2 macrophages, and increases inflammation.
Adipocyte‐selective deletion of Sirt1 exacerbates high‐fat diet‐induced insulin resistance and adipose tissue inflammation.
SIRT1‐deficient adipocytes cause increased macrophage recruitment and polarization versus pro‐inflammatory M1 subtypes.
NFATc1 is deacetylated by SIRT1 and thereby sustains expression of interleukin 4 in adipocytes.
EMBO Reports (2017) 18: 645–657
- Received August 10, 2016.
- Revision received February 5, 2017.
- Accepted February 7, 2017.
- © 2017 The Authors
- MYC‐driven inhibition of the glutamate‐cysteine ligase promotes glutathione depletion in liver cancer
- Brittany Anderton1,2,
- Roman Camarda1,2,
- Sanjeev Balakrishnan1,2,
- Asha Balakrishnan1,2,3,
- Rebecca A Kohnz4,
- Lionel Lim1,2,
- Kimberley J Evason5,
- Olga Momcilovic1,2,
- Klaus Kruttwig1,2,
- Qiang Huang6,
- Guowang Xu6,
- Daniel K Nomura4 and
- Andrei Goga (Andrei.goga{at}ucsf.edu)*,1,2
- 1Department of Cell and Tissue Biology, University of California, San Francisco, San Francisco, CA, USA
- 2Department of Medicine, University of California, San Francisco, San Francisco, CA, USA
- 3Department of Gastroenterology, Hepatology, and Endocrinology, Hannover Medical School, TWINCORE, Center for Experimental and Clinical Infection Research, Hannover, Germany
- 4Department of Nutritional Sciences and Toxicology, University of California, Berkeley, CA, USA
- 5Department of Pathology and Huntsman Cancer Institute, University of Utah, Salt Lake, UT, USA
- 6Key Laboratory of Separation Science for Analytical Chemistry, Dalian Institute of Chemical Physics, Chinese Academy of Sciences, Dalian, China
- ↵*Corresponding author. Tel: +1 415 476 4191; E‐mail: Andrei.goga{at}ucsf.edu
This study shows that MYC inhibits GCLC, the rate‐limiting enzyme of glutathione synthesis, via the microRNA miR‐18a in primary tumors. Therefore, MYC‐driven liver tumors with low total tissue levels of glutathione exhibit increased sensitivity to a potent oxidant.
Synopsis
This study shows that MYC inhibits GCLC, the rate‐limiting enzyme of glutathione synthesis, via the microRNA miR‐18a in primary tumors. Therefore, MYC‐driven liver tumors with low total tissue levels of glutathione exhibit increased sensitivity to a potent oxidant.
Six metabolic pathways deregulated by MYC in primary liver tumors are identified using integrated biochemical and gene expression analyses.
Total glutathione (GSH) levels are depleted in MYC‐driven liver tumors, which is associated with reduced glutathione synthesis.
GCLC, the rate‐limiting enzyme of GSH synthesis, is attenuated by the MYC‐induced miR‐18a.
Exogenous treatment of primary MYC liver tumors with the oxidant diquat specifically induces tumor cell death and diminishes MYC expression in surviving tumor cells.
EMBO Reports (2017) 18: 569–585
- Received July 15, 2016.
- Revision received January 8, 2017.
- Accepted January 13, 2017.
- © 2017 The Authors
- PKM2, cancer metabolism, and the road ahead
- 1David H. Koch Institute for Integrative Cancer Research and Department of Biology, Massachusetts Institute of Technology, Cambridge, MA, USA
- 2Howard Hughes Medical Institute, Massachusetts Institute of Technology, Cambridge, MA, USA
- 3Department of Medical Oncology, Dana‐Farber Cancer Institute, Boston, MA, USA
- ↵*Corresponding author. Tel: +1 617 252 1163; E‐mail: mvh{at}mit.edu
Isoforms of the glycolytic enzyme pyruvate kinase support tumor metabolism and growth. This review discusses PKM2 studies that have elucidated both normal and cancer cell metabolism.
EMBO Reports (2016) 17: 1721–1730
- Received September 3, 2016.
- Revision received October 10, 2016.
- Accepted October 17, 2016.
- © 2016 The Authors
- Loss of Nat4 and its associated histone H4 N‐terminal acetylation mediates calorie restriction‐induced longevity
- Diego Molina‐Serrano1,
- Vassia Schiza1,
- Christis Demosthenous1,
- Emmanouil Stavrou1,
- Jan Oppelt2,3,
- Dimitris Kyriakou1,
- Wei Liu4,
- Gertrude Zisser5,
- Helmut Bergler5,
- Weiwei Dang4 and
- Antonis Kirmizis (kirmizis{at}ucy.ac.cy)*,1
- 1Department of Biological Sciences, University of Cyprus, Nicosia, Cyprus
- 2CEITEC‐Central European Institute of Technology, Masaryk University, Brno, Czech Republic
- 3National Centre for Biomolecular Research, Masaryk University, Brno, Czech Republic
- 4Huffington Center on Aging, Baylor College of Medicine, Houston, TX, USA
- 5Institut für Molekulare Biowissenschaften, Karl‐Franzens‐Universität, Graz, Austria
- ↵*Corresponding author. Tel: +357 22 892678; E‐mail: kirmizis{at}ucy.ac.cy
Histone H4 N‐terminal acetylation (N‐acH4) catalyzed by Nat4 links calorie restriction and a specific transcriptional program that impacts on cellular lifespan.
Synopsis
Histone H4 N‐terminal acetylation (N‐acH4) catalyzed by Nat4 links calorie restriction and a specific transcriptional program that impacts on cellular lifespan.
Calorie restriction reduces the levels of Nat4 and thus the presence of N‐acH4 on chromatin.
Downregulation of N‐acH4 induces a cohort of stress response genes that promote cellular longevity.
Constitutive expression of Nat4 and maintenance of nucleosomal N‐acH4 levels compromises the longevity effect of calorie restriction.
EMBO Reports (2016) 17: 1829–1843
- Received April 12, 2016.
- Revision received September 21, 2016.
- Accepted September 30, 2016.
- © 2016 The Authors. Published under the terms of the CC BY 4.0 license
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.
- From HDACi to KDACi: we need to revisit non‐epigenetic pathways affected by inhibiting lysine deacetylases in therapy
Lysine deacetylases act on many other proteins apart from histones, with effects on metabolism and gene expression. We need to be cautious that therapeutically used KDACi have a much more widespread impact than anticipated.
- © 2016 The Authors
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