Metabolism
- Enzyme sub‐functionalization driven by regulation
The emergence of functional novelties during protein evolution has puzzled scientists for many years. Most proposed models focus on repeated duplication‐divergence cycles, but the entanglement of selection pressures acting on the control of transcriptional and enzymatic activity, for example, by metabolites, has not been addressed so far. In this issue of EMBO Reports, Noda‐Garcia et al [1] describe two glutamate dehydrogenase paralogs from Bacillus subtilis with very similar sequences and under two distinct modes of activity control. The functional divergence of these two enzymes during evolution is driven by an interlinked combination of differences between their enzymatic properties and their transcriptional regulation. This article thus illuminates another level of complexity in molecular evolution that may help understand the hitherto unexplained co‐existence of paralogous genes that at first sight appear to be functionally redundant.
See also: L Noda‐Garcia et al (July 2017)
A study in this issue shows how the co‐evolution of transcriptional and enzyme activity regulation contributes to the functional divergence of two Bacilli glutamate dehydrogenase paralogs.
- © 2017 The Authors
- High‐affinity cooperative Ca2+ binding by MICU1–MICU2 serves as an on–off switch for the uniporter
- Kimberli J Kamer1,2,
- Zenon Grabarek (grabarek{at}molbio.mgh.harvard.edu)*,2 and
- Vamsi K Mootha (vamsi_mootha{at}hms.harvard.edu)*,2,3,4
- 1Department of Chemistry and Chemical Biology, Harvard University, Cambridge, MA, USA
- 2Howard Hughes Medical Institute and Department of Molecular Biology, Massachusetts General Hospital, Boston, MA, USA
- 3Department of Systems Biology, Harvard Medical School, Boston, MA, USA
- 4Broad Institute, Cambridge, MA, USA
- ↵*
Corresponding author. Tel: +1 617 724 3151; E‐mail: grabarek{at}molbio.mgh.harvard.edu
Corresponding author. Tel: +1 617 643 3059; E‐mail: vamsi_mootha{at}hms.harvard.edu
The MICU1–MICU2 heterodimer binds Ca2+ cooperatively with high affinity, which sets a sharp threshold for the uniporter, and allows direct response to cytosolic Ca2+ signals. Interaction with cardiolipin facilitates tethering of MICU1–MICU2 to the inner membrane.
Synopsis
The MICU1–MICU2 heterodimer binds Ca2+ cooperatively with high affinity, which sets a sharp threshold for the uniporter, and allows direct response to cytosolic Ca2+ signals. Interaction with cardiolipin facilitates tethering of MICU1–MICU2 to the inner membrane.
MICU1 and MICU2 form a heterodimer, which binds Ca2+ with 620 nM affinity.
MICU1–MICU2 Ca2+ binding determines the threshold of the mitochondrial uniporter.
MICU1 and MICU2 bind cardiolipin irrespective of Ca2+, tethering the complex to the inner membrane.
- Received December 1, 2016.
- Revision received May 1, 2017.
- Accepted May 4, 2017.
- © 2017 The Authors
- Let's burn whatever you have: mitofusin 2 metabolically re‐wires brown adipose tissue
Brown adipose tissue (BAT) has received enormous scientific and lay attention in the recent past as its thermogenic, energy‐consuming capacities represent prime candidates for therapeutic interventions toward obesity, glucose intolerance, and diabetes even in humans. The overall positive effects of BAT activation and recruitment on systemic energy homeostasis have been largely attributed to the inherent ability of brown adipocytes to combust fatty acid and glucose energy substrates through mitochondrial uncoupling, driven by the unique expression of uncoupling protein 1 (UCP1). Two recent reports by Boutant et al and Mahdaviani et al now identify the GTPase mitofusin (Mfn) 2 as a key determinant of BAT thermogenic function that is largely independent of its previously described role in mitochondrial fusion [1,2].
See also: K Mahdaviani et al (July 2017) and M Boutant et al (June 2017)
Two studies in EMBO Reports and The EMBO Journal identify the GTPase mitofusin 2 as critical determinant of brown adipocyte tissue thermogenic function and insulin sensitivity.
- © 2017 The Authors
- Mfn2 deletion in brown adipose tissue protects from insulin resistance and impairs thermogenesis
- Kiana Mahdaviani1,2,
- Ilan Y Benador1,2,
- Shi Su1,
- Raffi A Gharakhanian1,
- Linsey Stiles1,2,
- Kyle M Trudeau1,2,
- Maria Cardamone3,
- Violeta Enríquez‐Zarralanga1,
- Eleni Ritou1,2,
- Tamar Aprahamian4,
- Marcus F Oliveira1,5,
- Barbara E Corkey1,
- Valentina Perissi3,
- Marc Liesa (mliesa{at}mednet.ucla.edu)*,1,2 and
- Orian S Shirihai (oshirihai{at}mednet.ucla.edu)*,1,2,6
- 1Obesity Research Center, Department of Medicine, Boston University School of Medicine, Boston, MA, USA
- 2Division of Endocrinology, Department of Medicine, David Geffen School of Medicine at UCLA, Los Angeles, CA, USA
- 3Biochemistry Department, Boston University School of Medicine, Boston, MA, USA
- 4Renal Section, Department of Medicine, Boston University School of Medicine, Boston, MA, USA
- 5Laboratório de Bioquímica de Resposta ao Estresse, Instituto de Bioquímica Médica Leopoldo de Meis, Universidade Federal do Rio de Janeiro, Rio de Janeiro, RJ, Brazil
- 6Department of Clinical Biochemistry, School of Medicine, Ben Gurion University, Beer‐Sheva, Israel
- ↵*
Corresponding author. Tel: +1 310‐206‐7319; E‐mail: mliesa{at}mednet.ucla.edu
Corresponding author. Tel: +1 617 230 8570; E‐mail: oshirihai{at}mednet.ucla.edu
Deletion of Mfn2 in BAT improves glucose tolerance under high fat diet while impairing cold‐induced thermogenesis. Therefore, BAT therapeutic potential to improve insulin sensitivity may be achieved independently of thermogenesis.
Synopsis
Deletion of Mfn2 in BAT improves glucose tolerance under high fat diet while impairing cold‐induced thermogenesis. Therefore, BAT therapeutic potential to improve insulin sensitivity may be achieved independently of thermogenesis.
Mfn2 in BAT is required to sustain body temperature after cold‐exposure.
Mfn2 deletion in BAT protects from obesity‐induced insulin resistance and increases whole body lipid oxidation.
In obesity, Mfn2 deletion in BAT promotes a gender‐specific remodeling of BAT mitochondria and metabolism to increase ATP synthesis capacity.
EMBO Reports (2017) 18: 1123–1138
- Received December 15, 2016.
- Revision received April 3, 2017.
- Accepted April 10, 2017.
- © 2017 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.
- 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.
EMBO Reports (2017) 18: 1150–1165
- 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.
EMBO Reports (2017) 18: 1139–1149
- 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
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