SUCLA2 Mutations Cause Global Protein Succinylation Contributing To
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Two Transgenic Mouse Models for Β-Subunit Components of Succinate-Coa Ligase Yielding Pleiotropic Metabolic Alterations
Two transgenic mouse models for -subunit components of succinate-CoA ligase yielding pleiotropic metabolic alterations Kacso, Gergely; Ravasz, Dora; Doczi, Judit; Németh, Beáta; Madgar, Ory; Saada, Ann; Ilin, Polina; Miller, Chaya; Ostergaard, Elsebet; Iordanov, Iordan; Adams, Daniel; Vargedo, Zsuzsanna; Araki, Masatake; Araki, Kimi; Nakahara, Mai; Ito, Haruka; Gál, Aniko; Molnár, Mária J; Nagy, Zsolt; Patocs, Attila; Adam-Vizi, Vera; Chinopoulos, Christos Published in: Biochemical Journal DOI: 10.1042/BCJ20160594 Publication date: 2016 Document version Publisher's PDF, also known as Version of record Document license: CC BY Citation for published version (APA): Kacso, G., Ravasz, D., Doczi, J., Németh, B., Madgar, O., Saada, A., Ilin, P., Miller, C., Ostergaard, E., Iordanov, I., Adams, D., Vargedo, Z., Araki, M., Araki, K., Nakahara, M., Ito, H., Gál, A., Molnár, M. J., Nagy, Z., ... Chinopoulos, C. (2016). Two transgenic mouse models for -subunit components of succinate-CoA ligase yielding pleiotropic metabolic alterations. Biochemical Journal, 473(20), 3463-3485. https://doi.org/10.1042/BCJ20160594 Download date: 02. okt.. 2021 Biochemical Journal (2016) 473 3463–3485 DOI: 10.1042/BCJ20160594 Research Article Two transgenic mouse models for β-subunit components of succinate-CoA ligase yielding pleiotropic metabolic alterations Gergely Kacso1,2, Dora Ravasz1,2, Judit Doczi1,2, Beáta Németh1,2, Ory Madgar1,2, Ann Saada3, Polina Ilin3, Chaya Miller3, Elsebet Ostergaard4, Iordan Iordanov1,5, Daniel Adams1,2, Zsuzsanna Vargedo1,2, Masatake -
Complex I Deficiency Due to Loss of Ndufs4 in the Brain Results
Complex I deficiency due to loss of Ndufs4 in the brain results in progressive encephalopathy resembling Leigh syndrome Albert Quintanaa,1, Shane E. Krusea,1, Raj P. Kapurb, Elisenda Sanzc, and Richard D. Palmitera,2 aHoward Hughes Medical Institute and Department of Biochemistry, University of Washington, Seattle, WA 98195; bDepartment of Laboratories, Seattle Children’s Hospital, Seattle, WA 98105; and cDepartment of Pharmacology, University of Washington, Seattle, WA 98195 Contributed by Richard D. Palmiter, May 5, 2010 (sent for review April 22, 2010) To explore the lethal, ataxic phenotype of complex I deficiency in least one intact Ndufs4 allele are indistinguishable from WT Ndufs4 knockout (KO) mice, we inactivated Ndufs4 selectively in mice, and they are sometimes used interchangeably with WT as neurons and glia (NesKO mice). NesKO mice manifested the same controls (CT). To examine the role of the CNS in pathology, we symptoms as KO mice including retarded growth, loss of motor restricted the inactivation of Ndufs4 gene to neurons and lox/lox ability, breathing abnormalities, and death by ∼7 wk. Progressive astroglial cells by crossing the Ndufs4 mice with mice neuronal deterioration and gliosis in specific brain areas corre- expressing Cre recombinase from the Nestin locus (19) to create sponded to behavioral changes as the disease advanced, with mice that we refer to as NesKO mice. We confirmed that Nestin- early involvement of the olfactory bulb, cerebellum, and vestibular Cre results in recombination primarily in the CNS by crossing the nuclei. Neurons, particularly in these brain regions, had aberrant mice with a Rosa26-reporter line and by PCR analysis of DNA mitochondrial morphology. -
Computational Modeling of Lysine Post-Translational Modification: an Overview Md
c and S eti ys h te nt m y s S B Hasan MM et al., Curr Synthetic Sys Biol 2018, 6:1 t i n o e l Current Synthetic and o r r g DOI: 10.4172/2332-0737.1000137 u y C ISSN: 2332-0737 Systems Biology CommentaryResearch Article OpenOpen Access Access Computational Modeling of Lysine Post-Translational Modification: An Overview Md. Mehedi Hasan 1*, Mst. Shamima Khatun2, and Hiroyuki Kurata1,3 1Department of Bioscience and Bioinformatics, Kyushu Institute of Technology, 680-4 Kawazu, Iizuka, Fukuoka 820-8502, Japan 2Department of Statistics, Laboratory of Bioinformatics, Rajshahi University-6205, Bangladesh 3Biomedical Informatics R&D Center, Kyushu Institute of Technology, 680-4 Kawazu, Iizuka, Fukuoka 820-8502, Japan Commentary hot spot for PTMs, and a number of protein lysine modifications could occur in both histone and non-histone proteins [11,12]. For instance, Living organisms have a magnificent ordered and complex lysine methylation in non-histone proteins can regulate the protein structure. In regulating the cellular functions, post-translational activity and protein structure stability [13]. In 2004, the Nobel Prize in modifications (PTMs) are critical molecular measures. They alter Chemistry was awarded jointly to Aaron Ciechanover, Avram Hershko protein conformation, modulating their activity, stability and and Irwin Rose for the discovery of lysine ubiquitin-mediated protein localization. Up to date, more than 300 types of PTMs are experimentally degradation [14]. discovered in vivo and in vitro pathways [1,2]. Major and common PTMs are methylation, ubiquitination, succinylation, phosphorylation, Moreover, in biological process, lysine can be modified by the glycosylation, acetylation, and sumoylation. -
Loss of Conserved Ubiquitylation Sites in Conserved Proteins During Human Evolution
INTERNATIONAL JOURNAL OF MOleCular meDICine 42: 2203-2212, 2018 Loss of conserved ubiquitylation sites in conserved proteins during human evolution DONGBIN PARK, CHUL JUN GOH, HYEIN KIM, JI SEOK LEE and YOONSOO HAHN Department of Life Science, Chung‑Ang University, Seoul 06974, Republic of Korea Received January 30, 2018; Accepted July 6, 2018 DOI: 10.3892/ijmm.2018.3772 Abstract. Ubiquitylation of lysine residues in proteins serves Introduction a pivotal role in the efficient removal of misfolded or unused proteins and in the control of various regulatory pathways Ubiquitylation, in which the highly conserved 76‑residue poly- by monitoring protein activity that may lead to protein peptide ubiquitin is covalently attached to a lysine residue of degradation. The loss of ubiquitylated lysines may affect substrate proteins, mediates the targeted destruction of ubiq- the ubiquitin‑mediated regulatory network and result in the uitylated proteins by the ubiquitin‑proteasome system (1‑4). emergence of novel phenotypes. The present study analyzed The ubiquitin‑mediated protein degradation pathway serves a mouse ubiquitylation data and orthologous proteins from crucial role in the efficient and specific removal of misfolded 62 mammals to identify 193 conserved ubiquitylation sites from proteins and certain key regulatory proteins (5,6). Ubiquitin 169 proteins that were lost in the Euarchonta lineage leading and other ubiquitin‑like proteins, including autophagy‑related to humans. A total of 8 proteins, including betaine homo- protein 8, Ubiquitin‑like -
Metabolomics-Assisted Proteomics Identifies Succinylation and SIRT5 As Important Regulators of Cardiac Function
Metabolomics-assisted proteomics identifies succinylation and SIRT5 as important regulators of cardiac function Sushabhan Sadhukhana, Xiaojing Liub,c,d, Dongryeol Ryue, Ornella D. Nelsona, John A. Stupinskif, Zhi Lia, Wei Cheng, Sheng Zhangg, Robert S. Weissf, Jason W. Locasaleb,c,d, Johan Auwerxe,1, and Hening Lina,h,1 aDepartment of Chemistry and Chemical Biology, Cornell University, Ithaca, NY 14853; bDuke Cancer Institute, Duke University School of Medicine, Durham, NC 27710; cDuke Molecular Physiology Institute, Duke University School of Medicine, Durham, NC 27710; dDepartment of Pharmacology and Cancer Biology, Duke University School of Medicine, Durham, NC 27710; eLaboratory of Integrative and Systems Physiology, School of Life Sciences, École Polytechnique Fédérale de Lausanne, 1015 Lausanne, Switzerland; fDepartment of Biomedical Sciences, Cornell University, Ithaca, NY 14853; gProteomics & Mass Spectrometry Facility, Institute of Biotechnology, Cornell University, Ithaca, NY 14853; and hHoward Hughes Medical Institute, Cornell University, Ithaca, NY 14853 Edited by Kevan M. Shokat, University of California, San Francisco, CA, and approved March 9, 2016 (received for review October 7, 2015) Cellular metabolites, such as acyl-CoA, can modify proteins, leading SIRT4 and SIRT5 have very weak deacetylase activities (14). SIRT5 to protein posttranslational modifications (PTMs). One such PTM is possesses unique enzymatic activity on hydrolyzing negatively lysine succinylation, which is regulated by sirtuin 5 (SIRT5). Although charged -
SUMO and Transcriptional Regulation: the Lessons of Large-Scale Proteomic, Modifomic and Genomic Studies
molecules Review SUMO and Transcriptional Regulation: The Lessons of Large-Scale Proteomic, Modifomic and Genomic Studies Mathias Boulanger 1,2 , Mehuli Chakraborty 1,2, Denis Tempé 1,2, Marc Piechaczyk 1,2,* and Guillaume Bossis 1,2,* 1 Institut de Génétique Moléculaire de Montpellier (IGMM), University of Montpellier, CNRS, Montpellier, France; [email protected] (M.B.); [email protected] (M.C.); [email protected] (D.T.) 2 Equipe Labellisée Ligue Contre le Cancer, Paris, France * Correspondence: [email protected] (M.P.); [email protected] (G.B.) Abstract: One major role of the eukaryotic peptidic post-translational modifier SUMO in the cell is transcriptional control. This occurs via modification of virtually all classes of transcriptional actors, which include transcription factors, transcriptional coregulators, diverse chromatin components, as well as Pol I-, Pol II- and Pol III transcriptional machineries and their regulators. For many years, the role of SUMOylation has essentially been studied on individual proteins, or small groups of proteins, principally dealing with Pol II-mediated transcription. This provided only a fragmentary view of how SUMOylation controls transcription. The recent advent of large-scale proteomic, modifomic and genomic studies has however considerably refined our perception of the part played by SUMO in gene expression control. We review here these developments and the new concepts they are at the origin of, together with the limitations of our knowledge. How they illuminate the SUMO-dependent Citation: Boulanger, M.; transcriptional mechanisms that have been characterized thus far and how they impact our view of Chakraborty, M.; Tempé, D.; SUMO-dependent chromatin organization are also considered. -
A High-Throughput Approach to Uncover Novel Roles of APOBEC2, a Functional Orphan of the AID/APOBEC Family
Rockefeller University Digital Commons @ RU Student Theses and Dissertations 2018 A High-Throughput Approach to Uncover Novel Roles of APOBEC2, a Functional Orphan of the AID/APOBEC Family Linda Molla Follow this and additional works at: https://digitalcommons.rockefeller.edu/ student_theses_and_dissertations Part of the Life Sciences Commons A HIGH-THROUGHPUT APPROACH TO UNCOVER NOVEL ROLES OF APOBEC2, A FUNCTIONAL ORPHAN OF THE AID/APOBEC FAMILY A Thesis Presented to the Faculty of The Rockefeller University in Partial Fulfillment of the Requirements for the degree of Doctor of Philosophy by Linda Molla June 2018 © Copyright by Linda Molla 2018 A HIGH-THROUGHPUT APPROACH TO UNCOVER NOVEL ROLES OF APOBEC2, A FUNCTIONAL ORPHAN OF THE AID/APOBEC FAMILY Linda Molla, Ph.D. The Rockefeller University 2018 APOBEC2 is a member of the AID/APOBEC cytidine deaminase family of proteins. Unlike most of AID/APOBEC, however, APOBEC2’s function remains elusive. Previous research has implicated APOBEC2 in diverse organisms and cellular processes such as muscle biology (in Mus musculus), regeneration (in Danio rerio), and development (in Xenopus laevis). APOBEC2 has also been implicated in cancer. However the enzymatic activity, substrate or physiological target(s) of APOBEC2 are unknown. For this thesis, I have combined Next Generation Sequencing (NGS) techniques with state-of-the-art molecular biology to determine the physiological targets of APOBEC2. Using a cell culture muscle differentiation system, and RNA sequencing (RNA-Seq) by polyA capture, I demonstrated that unlike the AID/APOBEC family member APOBEC1, APOBEC2 is not an RNA editor. Using the same system combined with enhanced Reduced Representation Bisulfite Sequencing (eRRBS) analyses I showed that, unlike the AID/APOBEC family member AID, APOBEC2 does not act as a 5-methyl-C deaminase. -
Ubiquitin Modifications
npg Cell Research (2016) 26:399-422. REVIEW www.nature.com/cr Ubiquitin modifications Kirby N Swatek1, David Komander1 1Medical Research Council Laboratory of Molecular Biology, Francis Crick Avenue, Cambridge, CB2 0QH, UK Protein ubiquitination is a dynamic multifaceted post-translational modification involved in nearly all aspects of eukaryotic biology. Once attached to a substrate, the 76-amino acid protein ubiquitin is subjected to further modi- fications, creating a multitude of distinct signals with distinct cellular outcomes, referred to as the ‘ubiquitin code’. Ubiquitin can be ubiquitinated on seven lysine (Lys) residues or on the N-terminus, leading to polyubiquitin chains that can encompass complex topologies. Alternatively or in addition, ubiquitin Lys residues can be modified by ubiq- uitin-like molecules (such as SUMO or NEDD8). Finally, ubiquitin can also be acetylated on Lys, or phosphorylated on Ser, Thr or Tyr residues, and each modification has the potential to dramatically alter the signaling outcome. While the number of distinctly modified ubiquitin species in cells is mind-boggling, much progress has been made to characterize the roles of distinct ubiquitin modifications, and many enzymes and receptors have been identified that create, recognize or remove these ubiquitin modifications. We here provide an overview of the various ubiquitin modifications present in cells, and highlight recent progress on ubiquitin chain biology. We then discuss the recent findings in the field of ubiquitin acetylation and phosphorylation, with a focus on Ser65-phosphorylation and its role in mitophagy and Parkin activation. Keywords: ubiquitin; proteasomal degradation; phosphorylation; post-translational modification; Parkin Cell Research (2016) 26:399-422. -
Exclusive Neuronal Expression of SUCLA2 in the Human Brain
Exclusive neuronal expression of SUCLA2 in the human brain Arpád Dobolyi1, Elsebet Ostergaard2, Attila G. Bagó1,3, Tamás Dóczi4, Miklós Palkovits1,5, Aniko Gál6, Mária J Molnár6, Vera Adam-Vizi7 and Christos Chinopoulos7 1Department of Anatomy, Histology and Embryology, Semmelweis University, Budapest, 1094, Hungary; 2Department of Clinical Genetics, Copenhagen University Hospital Rigshospitalet, Copenhagen, 2100, Denmark; 3National Institute of Neurosurgery, Budapest, 1145, Hungary; 4MTA-PTE Clinical MR Research Group, Department of Neurosurgery, University of Pécs, 7623, Pécs, Hungary; 5Human Brain Tissue Bank, Semmelweis University, Budapest, 1094, Hungary; 6Institute of Genomic Medicine and Rare Disorders, Semmelweis University, Budapest, 1083, Hungary; 7Department of Medical Biochemistry, Semmelweis University, Hungarian Academy of Sciences-SE Laboratory for Neurobiochemistry, Budapest, 1094, Hungary Address correspondence to: Dr. Christos Chinopoulos, Department of Medical Biochemistry, Semmelweis University, Budapest, Hungary. Tel: +361 4591500 ext. 60024, Fax: +361 2670031. E-mail: [email protected] ABSTRACT SUCLA2 encodes the ATP-forming subunit (A-SUCL- ) of succinyl-CoA ligase, an enzyme of the citric acid cycle. Mutations in SUCLA2 lead to a mitochondrial disorder manifesting as encephalomyopathy with dystonia, deafness and lesions in the basal ganglia. Despite the distinct brain pathology associated with SUCLA2 mutations, the precise localization of SUCLA2 protein has never been investigated. Here we show that immunoreactivity of A-SUCL- in surgical human cortical tissue samples was present exclusively in neurons, identified by their morphology and visualized by double labeling with a fluorescent Nissl dye. A-SUCL- immunoreactivity co-localized >99% with that of the d subunit of the mitochondrial F0-F1 ATP synthase. Specificity of the anti-A-SUCL- antiserum was verified by the absence of labeling in fibroblasts from a patient with a complete deletion of SUCLA2. -
Screen for Abnormal Mitochondrial Phenotypes in Mouse Embryonic Stem Cells Identifies a Model for Succinyl-Coa Ligase Deficiency and Mtdna Depletion Taraka R
© 2014. Published by The Company of Biologists Ltd | Disease Models & Mechanisms (2014) 7, 271-280 doi:10.1242/dmm.013466 RESOURCE ARTICLE Screen for abnormal mitochondrial phenotypes in mouse embryonic stem cells identifies a model for succinyl-CoA ligase deficiency and mtDNA depletion Taraka R. Donti1,‡, Carmen Stromberger1,*,‡, Ming Ge1, Karen W. Eldin2, William J. Craigen1,3 and Brett H. Graham1,§ ABSTRACT prevalence of mitochondrial disorders might be as high as 1 in 5000, Mutations in subunits of succinyl-CoA synthetase/ligase (SCS), a making mitochondrial disease one of the more common genetic component of the citric acid cycle, are associated with mitochondrial causes of encephalomyopathies and multisystem disease (Schaefer et encephalomyopathy, elevation of methylmalonic acid (MMA), and al., 2004; Elliott et al., 2008; Schaefer et al., 2008). Despite important mitochondrial DNA (mtDNA) depletion. A FACS-based retroviral- insights into clinical, biochemical and molecular features of these mediated gene trap mutagenesis screen in mouse embryonic stem disorders, the underlying molecular pathogenesis remains poorly (ES) cells for abnormal mitochondrial phenotypes identified a gene understood and no clearly effective therapies exist. Mitochondria trap allele of Sucla2 (Sucla2SAβgeo), which was used to generate contain their own genome that consists of a multicopy, ~16.4-kilobase transgenic mice. Sucla2 encodes the ADP-specific β-subunit isoform circular chromosome. This mitochondrial DNA (mtDNA) encodes 13 of SCS. Sucla2SAβgeo homozygotes exhibited recessive lethality, with polypeptides that are subunits of various respiratory chain complexes most mutants dying late in gestation (e18.5). Mutant placenta and as well as 22 tRNAs and two rRNAs required for mitochondrial embryonic (e17.5) brain, heart and muscle showed varying degrees protein translation. -
Succinyl-Coa Synthetase Deficiency in Siblings with Impaired Pyruvate Dehydrogenase Complex (PDC) and Other Oxidative
Harvard Medical School Succinyl-CoA synthetase deficiency in siblings with impaired pyruvate dehydrogenase complex (PDC) and other oxidative Boston Children’s Hospital enzymes in skeletal muscle without mtDNA depletion Cleveland Medical Center Xiaoping Huanga,, Jirair K. Bedoyanb,c,d,j, Didem Demirbasa, David J. Harrisa,e, Alexander Mironc, Simone Edelheitc, George Grahamed, Suzanne D. DeBrossebc,j, Lee-Jun Wongf, Charles L. Hoppeld,g,h, Douglas S. Kerrd,j, Irina Anselmi, and Gerard T. Berrya,e a Division of Genetics and Genomics, The Manton Center for Orphan Disease Research, Boston Children’s Hospital (BCH), Boston, MA, USA; b Center for Human Genetics, University Hospitals Cleveland Medical Center (UHCMC), Cleveland, OH, USA; c Department of Genetics and Genome Sciences, Case Western Reserve University (CWRU), Cleveland, OH, USA; d Center for Inherited Disorders of Energy Metabolism (CIDEM), UHCMC, Cleveland, OH, USA; e Department of Pediatrics, Harvard Medical School, Boston, MA, USA; f Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX, USA; g Department of Pharmacology, CWRU, Cleveland, OH, USA; h Department of Medicine, CWRU, Cleveland, OH, USA; I Department of Neurology, BCH, Boston, MA USA; and j Department of Pediatrics, CWRU, Cleveland, OH, USA. SUMMARY These authors contributed equally to this work. Mutations in SUCLA2 result in succinyl-CoA ligase (ATP-forming) or succinyl-CoA synthetase (ADP-forming) (A-SCS) deficiency, a mitochondrial tricarboxylic acid cycle disorder (Fig. 1). The phenotype associated with this gene defect is largely encephalomyopathy. We describe two siblings compound heterozygous for SUCLA2 mutations, c.985A>G (p.M329V) and c.920C>T (p.A307V), with parents confirmed as carriers of each mutation. -
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SAN TA C RUZ BI OTEC HNOL OG Y, INC . SUCLA2 (H-296): sc-68912 BACKGROUND PRODUCT SUCLA2 (succinate-CoA ligase, ADP-forming, β subunit), also known as A- β, Each vial contains 200 µg IgG in 1.0 ml of PBS with < 0.1% sodium azide SCS- βA or renal carcinoma antigen NY-REN-39, is a 463 amino acid mito - and 0.1% gelatin. chondrial matrix enzyme that belongs to the succinate/malate CoA ligase β subunit family. Widely expressed, SUCLA2 dimerizes with the SCS α sub - APPLICATIONS unit to form SCS-A, an essential component of the tricarboxylic acid cycle. SUCLA2 (H-296) is recommended for detection of SUCLA2 of mouse, rat and Defects in SUCLA2 may be involved in a group of autosomal recessive disor - human origin by Western Blotting (starting dilution 1:200, dilution range ders known as mitochondrial DNA depletion syndromes (MDSs) that are 1:100-1:1000), immunoprecipitation [1-2 µg per 100-500 µg of total protein characterized by a decrease in mitochondrial DNA copy numbers in affected (1 ml of cell lysate)], immunofluorescence (starting dilution 1:50, dilution tissues. Progressive external ophthalmoplegia (PEO), ataxia-neuropathy and range 1:50-1:500) and solid phase ELISA (starting dilution 1:30, dilution range mitochondrial neurogastrointestinal encephalomyopathy (MNGIE) may also be 1:30-1:3000). associated with mutations in SUCLA2. Two isoforms of SUCLA2 exists due to alternative splicing events. SUCLA2 (H-296) is also recommended for detection of SUCLA2 in additional species, including canine, bovine and porcine. REFERENCES Suitable for use as control antibody for SUCLA2 siRNA (h): sc-76598, SUCLA2 1.