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1
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Li Y, Tong F, Zhang Y, Cai Y, Ding J, Wang Q, Wang X. Neuropilin-2 Signaling Modulates Mossy Fiber Sprouting by Regulating Axon Collateral Formation Through CRMP2 in a Rat Model of Epilepsy. Mol Neurobiol 2022; 59:6817-6833. [PMID: 36044155 PMCID: PMC9525442 DOI: 10.1007/s12035-022-02995-0] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/22/2022] [Accepted: 08/07/2022] [Indexed: 11/30/2022]
Abstract
Programmed neural circuit formation constitutes the foundation for normal brain functions. Axon guidance cues play crucial roles in neural circuit establishment during development. Whether or how they contribute to maintaining the stability of networks in mature brains is seldom studied. Upon injury, neural rewiring could happen in adulthood, of which mossy fiber sprouting (MFS) is a canonical example. Here, we uncovered a novel role of axon guidance molecule family Sema3F/Npn-2 signaling in MFS and epileptogenesis in a rat model of epilepsy. Dentate gyrus-specific Npn-2 knockdown increased seizure activity in epileptic animals along with increased MFS. Hippocampal culture results suggested that Npn-2 signaling modulates MFS via regulating axon outgrowth and collateral formation. In addition, we discovered that Sema3F/Npn-2 signal through CRMP2 by regulating its phosphorylation in the process of MFS. Our work illustrated that Npn-2 signaling in adult epilepsy animals could potentially modulate seizure activity by controlling MFS. MFS constitutes the structural basis for abnormal electric discharge of neurons and recurrent seizures. Therapies targeting Npn-2 signaling could potentially have disease-modifying anti-epileptogenesis effects in epilepsy treatment.
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Affiliation(s)
- Yuxiang Li
- Department of Neurology, Zhongshan Hospital, Fudan University, Shanghai, China
| | - Fangchao Tong
- Department of Neurology, Zhongshan Hospital, Fudan University, Shanghai, China
| | - Yiying Zhang
- Department of Neurology, Zhongshan Hospital, Fudan University, Shanghai, China
| | - Yiying Cai
- Department of Neurology, Zhongshan Hospital, Fudan University, Shanghai, China
| | - Jing Ding
- Department of Neurology, Zhongshan Hospital, Fudan University, Shanghai, China
| | - Qiang Wang
- Department of Neurology, Zhongshan Hospital, Fudan University, Shanghai, China.
| | - Xin Wang
- Department of Neurology, Zhongshan Hospital, Fudan University, Shanghai, China. .,Department of The State Key Laboratory of Medical Neurobiology, MOE Frontiers Center for Brain Science, Institutes of Brain Science, Fudan University, Shanghai, China.
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2
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Rouyère C, Serrano T, Frémont S, Echard A. Oxidation and reduction of actin: Origin, impact in vitro and functional consequences in vivo. Eur J Cell Biol 2022; 101:151249. [PMID: 35716426 DOI: 10.1016/j.ejcb.2022.151249] [Citation(s) in RCA: 37] [Impact Index Per Article: 12.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/28/2022] [Revised: 05/13/2022] [Accepted: 06/06/2022] [Indexed: 11/15/2022] Open
Abstract
Actin is among the most abundant proteins in eukaryotic cells and assembles into dynamic filamentous networks regulated by many actin binding proteins. The actin cytoskeleton must be finely tuned, both in space and time, to fulfill key cellular functions such as cell division, cell shape changes, phagocytosis and cell migration. While actin oxidation by reactive oxygen species (ROS) at non-physiological levels are known for long to impact on actin polymerization and on the cellular actin cytoskeleton, growing evidence shows that direct and reversible oxidation/reduction of specific actin amino acids plays an important and physiological role in regulating the actin cytoskeleton. In this review, we describe which actin amino acid residues can be selectively oxidized and reduced in many different ways (e.g. disulfide bond formation, glutathionylation, carbonylation, nitration, nitrosylation and other oxidations), the cellular enzymes at the origin of these post-translational modifications, and the impact of actin redox modifications both in vitro and in vivo. We show that the regulated balance of oxidation and reduction of key actin amino acid residues contributes to the control of actin filament polymerization and disassembly at the subcellular scale and highlight how improper redox modifications of actin can lead to pathological conditions.
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Affiliation(s)
- Clémentine Rouyère
- Institut Pasteur, Université Paris Cité, CNRS UMR3691, Membrane Traffic and Cell Division Unit, 25-28 rue du Dr Roux, F-75015 Paris, France; Sorbonne Université, Collège Doctoral, F-75005 Paris, France
| | - Thomas Serrano
- Institut Pasteur, Université Paris Cité, CNRS UMR3691, Membrane Traffic and Cell Division Unit, 25-28 rue du Dr Roux, F-75015 Paris, France
| | - Stéphane Frémont
- Institut Pasteur, Université Paris Cité, CNRS UMR3691, Membrane Traffic and Cell Division Unit, 25-28 rue du Dr Roux, F-75015 Paris, France
| | - Arnaud Echard
- Institut Pasteur, Université Paris Cité, CNRS UMR3691, Membrane Traffic and Cell Division Unit, 25-28 rue du Dr Roux, F-75015 Paris, France.
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3
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Liu C, Qiao XZ, Wei ZH, Cao M, Wu ZY, Deng YC. Molecular typing of familial temporal lobe epilepsy. World J Psychiatry 2022; 12:98-107. [PMID: 35111581 PMCID: PMC8783165 DOI: 10.5498/wjp.v12.i1.98] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/28/2021] [Revised: 09/25/2021] [Accepted: 12/02/2021] [Indexed: 02/06/2023] Open
Abstract
The pathogenesis of temporal lobe epilepsy (TLE) was originally considered to be acquired. However, some reports showed that TLE was clustered in some families, indicating a genetic etiology. With the popularity of genetic testing technology, eleven different types of familial TLE (FTLE), including ETL1-ETL11, have been reported, of which ETL9-ETL11 had not yet been included in the OMIM database. These types of FTLE were caused by different genes/Loci and had distinct characteristics. ETL1, ETL7 and ETL10 were characterized by auditory, visual and aphasia seizures, leading to the diagnosis of familial lateral TLE. ETL2, ETL3 and ETL6 showed prominent autonomic symptom and automatism with or without hippocampal abnormalities, indicating a mesial temporal origin. Febrile seizures were common in FTLEs such as ETL2, ETL5, ETL6 and ETL11. ETL4 was diagnosed as occipitotemporal lobe epilepsy with a high incidence of migraine and visual aura. Considering the diversity and complexity of the symptoms of TLE, neurologists enquiring about the family history of epilepsy should ask whether the relatives of the proband had experienced unnoticeable seizures and whether there is a family history of other neurological diseases carefully. Most FTLE patients had a good prognosis with or without anti-seizure medication treatment, with the exception of patients with heterozygous mutations of the CPA6 gene. The pathogenic mechanism was diverse among these genes and spans disturbances of neuron development, differentiation and synaptic signaling. In this article, we describe the research progress on eleven different types of FTLE. The precise molecular typing of FTLE would facilitate the diagnosis and treatment of FTLE and genetic counseling for this disorder.
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Affiliation(s)
- Chao Liu
- Department of Neurology, The First Affiliated Hospital of Air Force Medical University, Xi'an 710032, Shaanxi Province, China
| | - Xiao-Zhi Qiao
- Department of Neurology, The First Affiliated Hospital of Air Force Medical University, Xi'an 710032, Shaanxi Province, China
| | - Zi-Han Wei
- Department of Neurology, The First Affiliated Hospital of Air Force Medical University, Xi'an 710032, Shaanxi Province, China
| | - Mi Cao
- Department of Neurology, The First Affiliated Hospital of Air Force Medical University, Xi'an 710032, Shaanxi Province, China
| | - Zhen-Yu Wu
- Department of Anatomy, Histology and Embryology and K.K. Leung Brain Research Centre, School of Basic Medicine, Air Force Medical University, Xi'an 710032, Shaanxi Province, China
| | - Yan-Chun Deng
- Department of Neurology, The First Affiliated Hospital of Air Force Medical University, Xi'an 710032, Shaanxi Province, China
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4
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Wu H, Yesilyurt HG, Yoon J, Terman JR. The MICALs are a Family of F-actin Dismantling Oxidoreductases Conserved from Drosophila to Humans. Sci Rep 2018; 8:937. [PMID: 29343822 PMCID: PMC5772675 DOI: 10.1038/s41598-017-17943-5] [Citation(s) in RCA: 34] [Impact Index Per Article: 4.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/07/2017] [Accepted: 11/30/2017] [Indexed: 12/27/2022] Open
Abstract
Cellular form and function – and thus normal development and physiology – are specified via proteins that control the organization and dynamic properties of the actin cytoskeleton. Using the Drosophila model, we have recently identified an unusual actin regulatory enzyme, Mical, which is directly activated by F-actin to selectively post-translationally oxidize and destabilize filaments – regulating numerous cellular behaviors. Mical proteins are also present in mammals, but their actin regulatory properties, including comparisons among different family members, remain poorly defined. We now find that each human MICAL family member, MICAL-1, MICAL-2, and MICAL-3, directly induces F-actin dismantling and controls F-actin-mediated cellular remodeling. Specifically, each human MICAL selectively associates with F-actin, which directly induces MICALs catalytic activity. We also find that each human MICAL uses an NADPH-dependent Redox activity to post-translationally oxidize actin’s methionine (M) M44/M47 residues, directly dismantling filaments and limiting new polymerization. Genetic experiments also demonstrate that each human MICAL drives F-actin disassembly in vivo, reshaping cells and their membranous extensions. Our results go on to reveal that MsrB/SelR reductase enzymes counteract each MICAL’s effect on F-actin in vitro and in vivo. Collectively, our results therefore define the MICALs as an important phylogenetically-conserved family of catalytically-acting F-actin disassembly factors.
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Affiliation(s)
- Heng Wu
- Departments of Neuroscience and Pharmacology, Harold C Simmons Comprehensive Cancer Center, The University of Texas Southwestern Medical Center, Dallas, TX, 75390, USA
| | - Hunkar Gizem Yesilyurt
- Departments of Neuroscience and Pharmacology, Harold C Simmons Comprehensive Cancer Center, The University of Texas Southwestern Medical Center, Dallas, TX, 75390, USA
| | - Jimok Yoon
- Departments of Neuroscience and Pharmacology, Harold C Simmons Comprehensive Cancer Center, The University of Texas Southwestern Medical Center, Dallas, TX, 75390, USA.,Drug Development Center, SK biopharmaceuticals Co. Ltd., Seongnam, 13494, Korea
| | - Jonathan R Terman
- Departments of Neuroscience and Pharmacology, Harold C Simmons Comprehensive Cancer Center, The University of Texas Southwestern Medical Center, Dallas, TX, 75390, USA.
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5
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van den Boogaard ML, Thijssen PE, Aytekin C, Licciardi F, Kıykım AA, Spossito L, Dalm VASH, Driessen GJ, Kersseboom R, de Vries F, van Ostaijen-Ten Dam MM, Ikinciogullari A, Dogu F, Oleastro M, Bailardo E, Daxinger L, Nain E, Baris S, van Tol MJD, Weemaes C, van der Maarel SM. Expanding the mutation spectrum in ICF syndrome: Evidence for a gender bias in ICF2. Clin Genet 2017; 92:380-387. [PMID: 28128455 DOI: 10.1111/cge.12979] [Citation(s) in RCA: 24] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/09/2016] [Revised: 01/13/2017] [Accepted: 01/23/2017] [Indexed: 12/16/2022]
Abstract
BACKGROUND Immunodeficiency, centromeric instability, and facial anomalies (ICF) syndrome is a rare, genetically heterogeneous, autosomal recessive disorder. Patients suffer from recurrent infections caused by reduced levels or absence of serum immunoglobulins. Genetically, 4 subtypes of ICF syndrome have been identified to date: ICF1 (DNMT3B mutations), ICF2 (ZBTB24 mutations), ICF3 (CDCA7 mutations), and ICF4 (HELLS mutations). AIM To study the mutation spectrum in ICF syndrome. MATERIALS AND METHODS Genetic studies were performed in peripheral blood lymphocyte DNA from suspected ICF patients and family members. RESULTS We describe 7 ICF1 patients and 6 novel missense mutations in DNMT3B, affecting highly conserved residues in the catalytic domain. We also describe 5 new ICF2 patients, one of them carrying a homozygous deletion of the complete ZBTB24 locus. In a meta-analysis of all published ICF cases, we observed a gender bias in ICF2 with 79% male patients. DISCUSSION The biallelic deletion of ZBTB24 provides strong support for the hypothesis that most ICF2 patients suffer from a ZBTB24 loss of function mechanism and confirms that complete absence of ZBTB24 is compatible with human life. This is in contrast to the observed early embryonic lethality in mice lacking functional Zbtb24. The observed gender bias seems to be restricted to ICF2 as it is not observed in the ICF1 cohort. CONCLUSION Our study expands the mutation spectrum in ICF syndrome and supports that DNMT3B and ZBTB24 are the most common disease genes.
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Affiliation(s)
- M L van den Boogaard
- Department of Human Genetics, Leiden University Medical Center, Leiden, The Netherlands
| | - P E Thijssen
- Department of Human Genetics, Leiden University Medical Center, Leiden, The Netherlands
- Department of Clinical Genetics, Leiden University Medical Center, Leiden, The Netherlands
| | - C Aytekin
- Department of Pediatric Immunology, Dr Sami Ulus Maternity and Children's Research and Educational Hospital, Ankara, Turkey
| | - F Licciardi
- Department of Paediatrics II, Regina Margherita Hospital Città della Salute e della Scienza di Torino, Torino, Italy
| | - A A Kıykım
- Pediatric Allergy and Immunology, Marmara University Pendik Training and Research Hospital, Istanbul, Turkey
| | - L Spossito
- Department of Immunology and Rheumatology, Hospital "J.P Garrahan", Buenos Aires, Argentina
| | - V A S H Dalm
- Department of Immunology, Erasmus MC, University Medical Centre, Rotterdam, The Netherlands
- Department of Internal Medicine, Division of Clinical Immunology, Erasmus MC, University Medical Centre, Rotterdam, The Netherlands
| | - G J Driessen
- Department of Paediatric Infectious Diseases, Erasmus MC, University Medical Centre, Rotterdam, The Netherlands
- Department of Pediatrics, Juliana Children's Hospital, Haga Teaching Hospital, The Hague, The Netherlands
| | - R Kersseboom
- Department of Clinical Genetics, Erasmus MC, University Medical Centre, Rotterdam, The Netherlands
- Medical service, Stichting Zuidwester, Middelharnis, The Netherlands
| | - F de Vries
- Department of Clinical Genetics, Erasmus MC, University Medical Centre, Rotterdam, The Netherlands
| | - M M van Ostaijen-Ten Dam
- Department of Pediatrics, Laboratory Immunology, Leiden University Medical Center, Leiden, The Netherlands
| | - A Ikinciogullari
- Department of Pediatric Immunology and Allergy, Ankara University School of Medicine, Ankara, Turkey
| | - F Dogu
- Department of Pediatric Immunology and Allergy, Ankara University School of Medicine, Ankara, Turkey
| | - M Oleastro
- Department of Immunology and Rheumatology, Hospital "J.P Garrahan", Buenos Aires, Argentina
| | - E Bailardo
- Department of Genetics, Hospital "J.P. Garrahan", Buenos Aires, Argentina
| | - L Daxinger
- Department of Human Genetics, Leiden University Medical Center, Leiden, The Netherlands
| | - E Nain
- Pediatric Allergy and Immunology, Marmara University Pendik Training and Research Hospital, Istanbul, Turkey
| | - S Baris
- Pediatric Allergy and Immunology, Marmara University Pendik Training and Research Hospital, Istanbul, Turkey
| | - M J D van Tol
- Department of Pediatrics, Laboratory Immunology, Leiden University Medical Center, Leiden, The Netherlands
| | - C Weemaes
- Department of Pediatric Infectious Diseases and Immunology, Radboud University Nijmegen Medical Centre, Nijmegen, The Netherlands
| | - S M van der Maarel
- Department of Human Genetics, Leiden University Medical Center, Leiden, The Netherlands
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6
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Vanoni MA. Structure-function studies of MICAL, the unusual multidomain flavoenzyme involved in actin cytoskeleton dynamics. Arch Biochem Biophys 2017; 632:118-141. [PMID: 28602956 DOI: 10.1016/j.abb.2017.06.004] [Citation(s) in RCA: 20] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/30/2017] [Revised: 05/27/2017] [Accepted: 06/05/2017] [Indexed: 12/11/2022]
Abstract
MICAL (from the Molecule Interacting with CasL) indicates a family of multidomain proteins conserved from insects to humans, which are increasingly attracting attention for their participation in the control of actin cytoskeleton dynamics, and, therefore, in the several related key processes in health and disease. MICAL is unique among actin binding proteins because it catalyzes a NADPH-dependent F-actin depolymerizing reaction. This unprecedented reaction is associated with its N-terminal FAD-containing domain that is structurally related to p-hydroxybenzoate hydroxylase, the prototype of aromatic monooxygenases, but catalyzes a strong NADPH oxidase activity in the free state. This review will focus on the known structural and functional properties of MICAL forms in order to provide an overview of the arguments supporting the current hypotheses on the possible mechanism of action of MICAL in the free and F-actin bound state, on the modulating effect of the CH, LIM, and C-terminal domains that follow the catalytic flavoprotein domain on the MICAL activities, as well as that of small molecules and proteins interacting with MICAL.
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Affiliation(s)
- Maria Antonietta Vanoni
- Department of Biosciences, Università degli Studi di Milano, Via Celoria 26, 20133 Milano, Italy.
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7
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Frémont S, Romet-Lemonne G, Houdusse A, Echard A. Emerging roles of MICAL family proteins - from actin oxidation to membrane trafficking during cytokinesis. J Cell Sci 2017; 130:1509-1517. [PMID: 28373242 DOI: 10.1242/jcs.202028] [Citation(s) in RCA: 55] [Impact Index Per Article: 6.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/31/2022] Open
Abstract
Cytokinetic abscission is the terminal step of cell division, leading to the physical separation of the two daughter cells. The exact mechanism mediating the final scission of the intercellular bridge connecting the dividing cells is not fully understood, but requires the local constriction of endosomal sorting complex required for transport (ESCRT)-III-dependent helices, as well as remodelling of lipids and the cytoskeleton at the site of abscission. In particular, microtubules and actin filaments must be locally disassembled for successful abscission. However, the mechanism that actively removes actin during abscission is poorly understood. In this Commentary, we will focus on the latest findings regarding the emerging role of the MICAL family of oxidoreductases in F-actin disassembly and describe how Rab GTPases regulate their enzymatic activity. We will also discuss the recently reported role of MICAL1 in controlling F-actin clearance in the ESCRT-III-mediated step of cytokinetic abscission. In addition, we will highlight how two other members of the MICAL family (MICAL3 and MICAL-L1) contribute to cytokinesis by regulating membrane trafficking. Taken together, these findings establish the MICAL family as a key regulator of actin cytoskeleton dynamics and membrane trafficking during cell division.
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Affiliation(s)
- Stéphane Frémont
- Membrane Traffic and Cell Division Lab, Cell Biology and Infection department, Institut Pasteur, 25-28 rue du Dr Roux, Paris CEDEX 15 75724, France .,Centre National de la Recherche Scientifique UMR3691, Paris 75015, France
| | - Guillaume Romet-Lemonne
- Institut Jacques Monod, CNRS, Université Paris Diderot, Université Sorbonne Paris Cité, Paris 75013, France
| | - Anne Houdusse
- Structural Motility, Institut Curie, PSL Research University, CNRS, UMR 144, Paris F-75005, France
| | - Arnaud Echard
- Membrane Traffic and Cell Division Lab, Cell Biology and Infection department, Institut Pasteur, 25-28 rue du Dr Roux, Paris CEDEX 15 75724, France .,Centre National de la Recherche Scientifique UMR3691, Paris 75015, France
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8
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Yoon J, Hung RJ, Terman JR. Characterizing F-actin Disassembly Induced by the Semaphorin-Signaling Component MICAL. Methods Mol Biol 2017; 1493:119-128. [PMID: 27787846 DOI: 10.1007/978-1-4939-6448-2_8] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/19/2022]
Abstract
The MICALs are a family of phylogenetically conserved cytoplasmic proteins that modulate numerous cellular behaviors and play critical roles in semaphorin-plexin signaling. Our recent results have revealed that the MICALs are an unusual family of actin regulatory proteins that use actin filaments (F-actin) as a direct substrate-controlling F-actin dynamics via stereospecific oxidation of conserved methionine (Met44 and Met47) residues within actin. In particular, the MICALs have a highly conserved flavoprotein monooxygenase (redox) enzymatic domain in their N-terminus that directly oxidizes and destabilizes F-actin. Here, we describe methods to characterize MICAL-mediated F-actin disassembly using in vitro assays with purified proteins.
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Affiliation(s)
- Jimok Yoon
- Departments of Neuroscience and Pharmacology and Neuroscience Graduate Program, The University of Texas Southwestern Medical Center, Dallas, TX, 75390, USA
| | - Ruei-Jiun Hung
- Departments of Neuroscience and Pharmacology and Neuroscience Graduate Program, The University of Texas Southwestern Medical Center, Dallas, TX, 75390, USA.,Department of Genetics, Harvard Medical School, Boston, MA, 02115, USA
| | - Jonathan R Terman
- Departments of Neuroscience and Pharmacology, The University of Texas Southwestern Medical Center, Dallas, TX, 75390, USA.
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9
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Wilson C, Terman JR, González-Billault C, Ahmed G. Actin filaments-A target for redox regulation. Cytoskeleton (Hoboken) 2016; 73:577-595. [PMID: 27309342 DOI: 10.1002/cm.21315] [Citation(s) in RCA: 62] [Impact Index Per Article: 6.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/20/2016] [Revised: 06/03/2016] [Accepted: 06/13/2016] [Indexed: 12/21/2022]
Abstract
Actin and its ability to polymerize into dynamic filaments is critical for the form and function of cells throughout the body. While multiple proteins have been characterized as affecting actin dynamics through noncovalent means, actin and its protein regulators are also susceptible to covalent modifications of their amino acid residues. In this regard, oxidation-reduction (Redox) intermediates have emerged as key modulators of the actin cytoskeleton with multiple different effects on cellular form and function. Here, we review work implicating Redox intermediates in post-translationally altering actin and discuss what is known regarding how these alterations affect the properties of actin. We also focus on two of the best characterized enzymatic sources of these Redox intermediates-the NADPH oxidase NOX and the flavoprotein monooxygenase MICAL-and detail how they have both been identified as altering actin, but share little similarity and employ different means to regulate actin dynamics. Finally, we discuss the role of these enzymes and redox signaling in regulating the actin cytoskeleton in vivo and highlight their importance for neuronal form and function in health and disease. © 2016 Wiley Periodicals, Inc.
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Affiliation(s)
- Carlos Wilson
- Department of Biology, Faculty of Sciences, Universidad De Chile, Las Palmeras 3425, Santiago, 7800024, Chile.,Center for Geroscience, Brain Health and Metabolism, Santiago, Chile
| | - Jonathan R Terman
- Department of Neuroscience, The University of Texas Southwestern Medical Center, Dallas, Texas, 75390. .,Department of Pharmacology, The University of Texas Southwestern Medical Center, Dallas, Texas, 75390.
| | - Christian González-Billault
- Department of Biology, Faculty of Sciences, Universidad De Chile, Las Palmeras 3425, Santiago, 7800024, Chile. .,Center for Geroscience, Brain Health and Metabolism, Santiago, Chile. .,The Buck Institute for Research on Aging, Novato, California 94945.
| | - Giasuddin Ahmed
- Department of Neuroscience, The University of Texas Southwestern Medical Center, Dallas, Texas, 75390.,Department of Pharmacology, The University of Texas Southwestern Medical Center, Dallas, Texas, 75390
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10
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Zhang Y, Liu J, Luan G, Wang X. Inhibition of the small GTPase Cdc42 in regulation of epileptic-seizure in rats. Neuroscience 2015; 289:381-91. [PMID: 25595978 DOI: 10.1016/j.neuroscience.2014.12.059] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/02/2014] [Revised: 12/16/2014] [Accepted: 12/16/2014] [Indexed: 11/28/2022]
Abstract
Altered expression of neuronal cytoskeletal proteins are known to play an important role in hyper-excitability of neurons in patients and animal models of epilepsy. Our previous work showed that cell division cycle 42 GTP-binding protein (Cdc42), a small GTPase of the Rho-subfamily, is significantly increased in the brain tissue of patients with temporal lobe epilepsy (TLE) and in the brain tissues of the epileptic model of rats. However, whether inhibition of Cdc42 can modify epileptic seizures has not been investigated. In this study, using a pilocarpine-induced epileptic model, we found that pretreatment with ML141, a specific inhibitor of Cdc42, reduces seizure severity. Whole-cell patch-clamp recording on CA1 pyramidal neurons in hippocampal slices from pilocarpine-induced epileptic model demonstrated that ML141 significantly inhibits the frequency of action potentials (APs), increases the amplitude and frequency of miniature inhibitory postsynaptic currents (mIPSCs), and increases the amplitude of evoked inhibitory postsynaptic currents (eIPSCs). However, ML141 did not have an impact on the miniature excitatory postsynaptic currents (mEPSCs). Our results are the first to indicate that Cdc42 plays an important role in the onset and progression of epileptic-seizures by regulating synaptic inhibition.
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Affiliation(s)
- Y Zhang
- Department of Neurology, The First Affiliated Hospital of Chongqing Medical University, Chongqing Key Laboratory of Neurology, 1 Youyi Road, Chongqing 400016, China
| | - J Liu
- Department of Neurology, The First Affiliated Hospital of Chongqing Medical University, Chongqing Key Laboratory of Neurology, 1 Youyi Road, Chongqing 400016, China
| | - G Luan
- Center of Epilepsy, Beijing Institute for Brain Disorders, China
| | - X Wang
- Department of Neurology, The First Affiliated Hospital of Chongqing Medical University, Chongqing Key Laboratory of Neurology, 1 Youyi Road, Chongqing 400016, China.
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11
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Giridharan SSP, Caplan S. MICAL-family proteins: Complex regulators of the actin cytoskeleton. Antioxid Redox Signal 2014; 20:2059-73. [PMID: 23834433 PMCID: PMC3993057 DOI: 10.1089/ars.2013.5487] [Citation(s) in RCA: 85] [Impact Index Per Article: 7.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/01/2023]
Abstract
SIGNIFICANCE The molecules interacting with CasL (MICAL) family members participate in a multitude of activities, including axonal growth cone repulsion, membrane trafficking, apoptosis, and bristle development in flies. An interesting feature of MICAL proteins is the presence of an N-terminal flavo-mono-oxygenase domain. This mono-oxygenase domain generates redox potential with which MICALs can either oxidize proteins or produce reactive oxygen species (ROS). Actin is one such protein that is affected by MICAL function, leading to dramatic cytoskeletal rearrangements. This review describes the MICAL-family members, and discusses their mechanisms of actin-binding and regulation of actin cytoskeleton organization. RECENT ADVANCES Recent studies show that MICALs directly induce oxidation of actin molecules, leading to actin depolymerization. ROS production by MICALs also causes oxidation of collapsin response mediator protein-2, a microtubule assembly promoter, which subsequently undergoes phosphorylation. CRITICAL ISSUES MICAL proteins oxidize proteins through two mechanisms: either directly by oxidizing methionine residues or indirectly via the production of ROS. It remains unclear whether MICAL proteins employ both mechanisms or whether the activity of MICAL-family proteins might vary with different substrates. FUTURE DIRECTIONS The identification of additional substrates oxidized by MICAL will shed new light on MICAL protein function. Additional directions include expanding studies toward the MICAL-like homologs that lack flavin adenine dinucleotide domains and oxidation activity.
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Affiliation(s)
- Sai Srinivas Panapakkam Giridharan
- Department of Biochemistry and Molecular Biology, and the Pamela and Fred Buffett Cancer Center, University of Nebraska Medical Center , Omaha, Nebraska
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12
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MICAL, the flavoenzyme participating in cytoskeleton dynamics. Int J Mol Sci 2013; 14:6920-59. [PMID: 23535333 PMCID: PMC3645671 DOI: 10.3390/ijms14046920] [Citation(s) in RCA: 23] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/02/2012] [Revised: 03/02/2013] [Accepted: 03/11/2013] [Indexed: 01/01/2023] Open
Abstract
MICAL (from the Molecule Interacting with CasL) indicates a family of recently discovered cytosolic, multidomain proteins, which uniquely couple an N-terminal FAD-containing monooxygenase-like domain to typical calponine homology, LIM and coiled-coil protein-interaction modules. Genetic and cell biology approaches have demonstrated an essential role of the catalytic activity of the monooxygenase-like domain in transducing the signal initiated by semaphorins interaction with their plexin receptors, which results in local actin cytoskeleton disassembly as part of fundamental processes that include differentiation, migration and cell-cell contacts in neuronal and non-neuronal cell types. This review focuses on the structure-function relations of the MICAL monooxygenase-like domain as they are emerging from the available in vitro studies on mouse, human and Drosophila MICAL forms that demonstrated a NADPH-dependent actin depolymerizing activity of MICAL. With Drosophila MICAL forms, actin depolymerization was demonstrated to be associated to conversion of Met44 to methionine sulfone through a postulated hydroxylating reaction. Arguments supporting the concept that MICAL effect on F-actin may be reversible will be discussed.
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Wang L, Luo J, Fang M, Jiang G, Zhang X, Yu W, Wang X. A new trick of INPP4A: Decreased expression of INPP4A in patients with temporal lobe epilepsy and pilocarpine-induced rat model. Synapse 2012; 66:533-41. [DOI: 10.1002/syn.21540] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/15/2011] [Revised: 01/12/2012] [Accepted: 01/13/2012] [Indexed: 11/06/2022]
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Down-Regulation of CRMP-1 in Patients with Epilepsy and a Rat Model. Neurochem Res 2012; 37:1381-91. [DOI: 10.1007/s11064-012-0712-6] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/21/2011] [Accepted: 01/19/2012] [Indexed: 12/12/2022]
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Hung RJ, Terman JR. Extracellular inhibitors, repellents, and semaphorin/plexin/MICAL-mediated actin filament disassembly. Cytoskeleton (Hoboken) 2011; 68:415-33. [PMID: 21800438 PMCID: PMC3612987 DOI: 10.1002/cm.20527] [Citation(s) in RCA: 55] [Impact Index Per Article: 3.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/18/2011] [Accepted: 07/21/2011] [Indexed: 01/29/2023]
Abstract
Multiple extracellular signals have been identified that regulate actin dynamics within motile cells, but how these instructive cues present on the cell surface exert their precise effects on the internal actin cytoskeleton is still poorly understood. One particularly interesting class of these cues is a group of extracellular proteins that negatively alter the movement of cells and their processes. Over the years, these types of events have been described using a variety of terms and herein we provide an overview of inhibitory/repulsive cellular phenomena and highlight the largest known protein family of repulsive extracellular cues, the Semaphorins. Specifically, the Semaphorins (Semas) utilize Plexin cell-surface receptors to dramatically collapse the actin cytoskeleton and we summarize what is known of the direct molecular and biochemical mechanisms of Sema-triggered actin filament (F-actin) disassembly. We also discuss new observations from our lab that reveal that the multidomain oxidoreductase (Redox) enzyme Molecule Interacting with CasL (MICAL), an important mediator of Sema/Plexin repulsion, is a novel F-actin disassembly factor. Our results indicate that MICAL triggers Sema/Plexin-mediated reorganization of the F-actin cytoskeleton and suggest a role for specific Redox signaling events in regulating actin dynamics.
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Affiliation(s)
- Ruei-Jiun Hung
- Departments of Neuroscience and Pharmacology, and Neuroscience Graduate Program, Harold C. Simmons Comprehensive Cancer Center, The University of Texas Southwestern Medical Center, Dallas, TX 75390, USA
| | - Jonathan R. Terman
- Departments of Neuroscience and Pharmacology, and Neuroscience Graduate Program, Harold C. Simmons Comprehensive Cancer Center, The University of Texas Southwestern Medical Center, Dallas, TX 75390, USA
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Peng X, Zhang X, Wang L, Zhu Q, Luo J, Wang W, Wang X. Gelsolin in Cerebrospinal Fluid as a Potential Biomarker of Epilepsy. Neurochem Res 2011; 36:2250-8. [DOI: 10.1007/s11064-011-0549-4] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/04/2011] [Revised: 07/03/2011] [Accepted: 07/12/2011] [Indexed: 01/03/2023]
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