The Experts below are selected from a list of 360 Experts worldwide ranked by ideXlab platform
Jonathan S Stamler - One of the best experts on this subject based on the ideXlab platform.
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A Multiplex Enzymatic Machinery for Cellular Protein S-Nitrosylation
Molecular Cell, 2018Co-Authors: Divya Seth, Alfred Hausladen, Yajuan Wang, Douglas T. Hess, Liwen Wang, Jonathan S StamlerAbstract:Summary S-Nitrosylation, the oxidative modification of Cys residues by nitric oxide (NO) to form S-nitrosothiols (SNOs), modifies all main classes of proteins and provides a fundamental redox-based cellular signaling mechanism. However, in contrast to other post-translational protein modifications, S-Nitrosylation is generally considered to be non-enzymatic, involving multiple chemical routes. We report here that endogenous protein S-Nitrosylation in the model organism E. coli depends principally upon the enzymatic activity of the hybrid cluster protein Hcp, employing NO produced by nitrate reductase. Anaerobiosis on nitrate induces both Hcp and nitrate reductase, thereby resulting in the S-Nitrosylation-dependent assembly of a large interactome including enzymes that generate NO (NO synthase), synthesize SNO-proteins (SNO synthase), and propagate SNO-based signaling (trans-nitrosylases) to regulate cell motility and metabolism. Thus, protein S-Nitrosylation by NO in E. coli is essentially enzymatic, and the potential generality of the multiplex enzymatic mechanism that we describe may support a re-conceptualization of NO-based cellular signaling.
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protein s nitrosylation determinants of specificity and enzymatic regulation of s nitrosothiol based signaling
Antioxidants & Redox Signaling, 2018Co-Authors: Colin T. Stomberski, Jonathan S Stamler, Douglas T. HessAbstract:Abstract Significance: Protein S-Nitrosylation, the oxidative modification of cysteine by nitric oxide (NO) to form protein S-nitrosothiols (SNOs), mediates redox-based signaling that conveys, in large part, the ubiquitous influence of NO on cellular function. S-Nitrosylation regulates protein activity, stability, localization, and protein–protein interactions across myriad physiological processes, and aberrant S-Nitrosylation is associated with diverse pathophysiologies. Recent Advances: It is recently recognized that S-Nitrosylation endows S-nitroso-protein (SNO-proteins) with S-nitrosylase activity, that is, the potential to trans-S-nitrosylate additional proteins, thereby propagating SNO-based signals, analogous to kinase-mediated signaling cascades. In addition, it is increasingly appreciated that cellular S-Nitrosylation is governed by dynamically coupled equilibria between SNO-proteins and low-molecular-weight SNOs, which are controlled by a growing set of enzymatic denitrosylases comprising two ma...
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Polyglutamine Tract Expansion Increases S-Nitrosylation of Huntingtin and Ataxin-1.
PLOS ONE, 2016Co-Authors: Divya Seth, Jonathan S Stamler, Fabio V. Fonseca, Liwen Wang, Tsan Sam Xiao, Phillip Gruber, Alan M. TartakoffAbstract:Expansion of the polyglutamine (polyQ) tract in the huntingtin (Htt) protein causes Huntington's disease (HD), a fatal inherited movement disorder linked to neurodegeneration in the striatum and cortex. S-Nitrosylation and S-acylation of cysteine residues regulate many functions of cytosolic proteins. We therefore used a resin-assisted capture approach to identify these modifications in Htt. In contrast to many proteins that have only a single S-Nitrosylation or S-acylation site, we identified sites along much of the length of Htt. Moreover, analysis of cells expressing full-length Htt or a large N-terminal fragment of Htt shows that polyQ expansion strongly increases Htt S-Nitrosylation. This effect appears to be general since it is also observed in Ataxin-1, which causes spinocerebellar ataxia type 1 (SCA1) when its polyQ tract is expanded. Overexpression of nitric oxide synthase increases the S-Nitrosylation of normal Htt and the frequency of conspicuous juxtanuclear inclusions of Htt N-terminal fragments in transfected cells. Taken together with the evidence that S-Nitrosylation of Htt is widespread and parallels polyQ expansion, these subcellular changes show that S-Nitrosylation affects the biology of this protein in vivo.
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s nitrosylation of the mitochondrial chaperone trap1 sensitizes hepatocellular carcinoma cells to inhibitors of succinate dehydrogenase
Cancer Research, 2016Co-Authors: Salvatore Rizza, Simone Cardaci, Costanza Montagna, Giuseppina Di Giacomo, Daniela De Zio, Emiliano Maiani, Virginia Sanchezquiles, Blagoy Blagoev, Andrea Rasola, Jonathan S StamlerAbstract:S-nitrosoglutathione reductase (GSNOR) represents the best-documented denitrosylase implicated in regulating the levels of proteins posttranslationally modified by nitric oxide on cysteine residues by S-Nitrosylation. GSNOR controls a diverse array of physiologic functions, including cellular growth and differentiation, inflammation, and metabolism. Chromosomal deletion of GSNOR results in pathologic protein S-Nitrosylation that is implicated in human hepatocellular carcinoma (HCC). Here we identify a metabolic hallmark of aberrant S-Nitrosylation in HCC and exploit it for therapeutic gain. We find that hepatocyte GSNOR deficiency is characterized by mitochondrial alteration and by marked increases in succinate dehydrogenase (SDH) levels and activity. We find that this depends on the selective S-Nitrosylation of Cys(501) in the mitochondrial chaperone TRAP1, which mediates its degradation. As a result, GSNOR-deficient cells and tumors are highly sensitive to SDH inhibition, namely to α-tocopheryl succinate, an SDH-targeting molecule that induced RIP1/PARP1-mediated necroptosis and inhibited tumor growth. Our work provides a specific molecular signature of aberrant S-Nitrosylation in HCC, a novel molecular target in SDH, and a first-in-class therapy to treat the disease. Cancer Res; 76(14); 4170-82. ©2016 AACR.
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Identification of S-nitroso-CoA reductases that regulate protein S-Nitrosylation.
Proceedings of the National Academy of Sciences of the United States of America, 2014Co-Authors: Puneet Anand, Alfred Hausladen, Yajuan Wang, Guofang Zhang, Colin T. Stomberski, Henri Brunengraber, Douglas T. Hess, Jonathan S StamlerAbstract:Coenzyme A (CoA) mediates thiol-based acyl-group transfer (acetylation and palmitoylation). However, a role for CoA in the thiol-based transfer of NO groups (S-Nitrosylation) has not been considered. Here we describe protein S-Nitrosylation in yeast (heretofore unknown) that is mediated by S-nitroso-CoA (SNO-CoA). We identify a specific SNO-CoA reductase encoded by the alcoholdehydrogenase 6 (ADH6) gene and show that deletion of ADH6 increases cellular S-Nitrosylation and alters CoA metabolism. Further, we report that Adh6, acting as a selective SNO-CoA reductase, protects acetoacetyl–CoA thiolase from inhibitory S-Nitrosylation and thereby affects sterol biosynthesis. Thus, Adh6-regulated, SNO-CoA–mediated protein S-Nitrosylation provides a regulatory mechanism paralleling protein acetylation. We also find that SNO-CoA reductases are present from bacteria to mammals, and we identify aldo-keto reductase 1A1 as the mammalian functional analog of Adh6. Our studies reveal a novel functional class of enzymes that regulate protein S-Nitrosylation from yeast to mammals and suggest that SNO-CoA–mediated S-Nitrosylation may subserve metabolic regulation.
Harry Ischiropoulos - One of the best experts on this subject based on the ideXlab platform.
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protein microarray characterization of the s nitrosoproteome
Molecular & Cellular Proteomics, 2014Co-Authors: Yun Il Lee, Paschalis-Thomas Doulias, Daniel Giovinazzo, Ho Chul Kang, Yunjong Lee, Jun Seop Jeong, Zhi Xie, Mehdi Ghasemi, Harry IschiropoulosAbstract:Nitric oxide (NO) mediates a substantial part of its physiologic functions via S-Nitrosylation, however the cellular substrates for NO-mediated S-Nitrosylation are largely unknown. Here we describe the S-nitrosoproteome using a high-density protein microarray chip containing 16,368 unique human proteins. We identified 834 potentially S-nitrosylated human proteins. Using a unique and highly specific labeling and affinity capture of S-nitrosylated proteins, 138 cysteine residues on 131 peptides in 95 proteins were determined, defining critical sites of NO's actions. Of these cysteine residues 113 are novel sites of S-Nitrosylation. A consensus sequence motif from these 834 proteins for S-Nitrosylation was identified, suggesting that the residues flanking the S-nitrosylated cysteine are likely to be the critical determinant of whether the cysteine is S-nitrosylated. We identify eight ubiquitin E3 ligases, RNF10, RNF11, RNF41, RNF141, RNF181, RNF208, WWP2, and UBE3A, whose activities are modulated by S-Nitrosylation, providing a unique regulatory mechanism of the ubiquitin proteasome system. These results define a new and extensive set of proteins that are susceptible to NO regulation via S-Nitrosylation. Similar approaches could be used to identify other post-translational modification proteomes.
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regulation of protein function and signaling by reversible cysteine s nitrosylation
Journal of Biological Chemistry, 2013Co-Authors: Neal S Gould, Paschalis-Thomas Doulias, Margarita Tenopoulou, Karthik Raju, Harry IschiropoulosAbstract:NO is a versatile free radical that mediates numerous biological functions within every major organ system. A molecular pathway by which NO accomplishes functional diversity is the selective modification of protein cysteine residues to form S-nitrosocysteine. This post-translational modification, S-Nitrosylation, impacts protein function, stability, and location. Despite considerable advances with individual proteins, the in vivo biological chemistry, the structural elements that govern the selective S-Nitrosylation of cysteine residues, and the potential overlap with other redox modifications are unknown. In this minireview, we explore the functional features of S-Nitrosylation at the proteome level and the structural diversity of endogenously modified residues, and we discuss the potential overlap and complementation that may exist with other cysteine modifications.
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nitric oxide regulates mitochondrial fatty acid metabolism through reversible protein s nitrosylation
Science Signaling, 2013Co-Authors: Paschalis-Thomas Doulias, Margarita Tenopoulou, Jennifer L Greene, Karthik Raju, Harry IschiropoulosAbstract:Cysteine S-Nitrosylation is a posttranslational modification by which nitric oxide regulates protein function and signaling. Studies of individual proteins have elucidated specific functional roles for S-Nitrosylation, but knowledge of the extent of endogenous S-Nitrosylation, the sites that are nitrosylated, and the regulatory consequences of S-Nitrosylation remains limited. We used mass spectrometry-based methodologies to identify 1011 S-nitrosocysteine residues in 647 proteins in various mouse tissues. We uncovered selective S-Nitrosylation of enzymes participating in glycolysis, gluconeogenesis, tricarboxylic acid cycle, and oxidative phosphorylation, indicating that this posttranslational modification may regulate metabolism and mitochondrial bioenergetics. S-Nitrosylation of the liver enzyme VLCAD [very long chain acyl-coenzyme A (CoA) dehydrogenase] at Cys(238), which was absent in mice lacking endothelial nitric oxide synthase, improved its catalytic efficiency. These data implicate protein S-Nitrosylation in the regulation of β-oxidation of fatty acids in mitochondria.
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proteomic identification of s nitrosylated golgi proteins new insights into endothelial cell regulation by enos derived no
PLOS ONE, 2012Co-Authors: Panjamaporn Sangwung, Harry Ischiropoulos, William C Sessa, Todd M Greco, Yanzhuang Wang, Yasuko IwakiriAbstract:Background Endothelial nitric oxide synthase (eNOS) is primarily localized on the Golgi apparatus and plasma membrane caveolae in endothelial cells. Previously, we demonstrated that protein S-Nitrosylation occurs preferentially where eNOS is localized. Thus, in endothelial cells, Golgi proteins are likely to be targets for S-Nitrosylation. The aim of this study was to identify S-nitrosylated Golgi proteins and attribute their S-Nitrosylation to eNOS-derived nitric oxide in endothelial cells.
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lymphocyte development requires s nitrosoglutathione reductase
Journal of Immunology, 2010Co-Authors: Zhiyong Yang, Zhien Wang, Paschalis-Thomas Doulias, Harry Ischiropoulos, Richard M LocksleyAbstract:NO is critical to immunity, but its role in the development of the immune system is unknown. In this study, we show that S-nitrosoglutathione reductase (GSNOR), a protein key to the control of protein S-Nitrosylation, is important for the development of lymphocytes. Genetic deletion of GSNOR in mice results in significant decrease in both T and B lymphocytes in the periphery. In thymus, GSNOR deficiency causes excessive protein S-Nitrosylation, increases apoptosis, and reduces the number of CD4 single-positive thymocytes. Lymphopenia and increase in S-Nitrosylation and apoptosis in GSNOR-deficient mice are largely abolished by genetic deletion of inducible NO synthase. Furthermore, the protection of lymphocyte development by GSNOR is apparently intrinsic to hematopoietic cells. Thus, GSNOR, likely through regulation of S-Nitrosylation and apoptosis, physiologically plays a protective role in the development of the immune system.
Paschalis-Thomas Doulias - One of the best experts on this subject based on the ideXlab platform.
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s nitrosylation of calcium handling proteins in cardiac adrenergic signaling and hypertrophy
Circulation Research, 2015Co-Authors: Tomoya Irie, Patrick Sips, Shinichi Kai, Kotaro Kida, Kohei Ikeda, Shuichi Hirai, Kasra Moazzami, Pawina Jiramongkolchai, D Bloch, Paschalis-Thomas DouliasAbstract:Rationale:The regulation of calcium (Ca2+) homeostasis by β-adrenergic receptor (βAR) activation provides the essential underpinnings of sympathetic regulation of myocardial function, as well as a basis for understanding molecular events that result in hypertrophic signaling and heart failure. Sympathetic stimulation of the βAR not only induces protein phosphorylation but also activates nitric oxide–dependent signaling, which modulates cardiac contractility. Nonetheless, the role of nitric oxide in βAR-dependent regulation of Ca2+ handling has not yet been explicated fully. Objective:To elucidate the role of protein S-Nitrosylation, a major transducer of nitric oxide bioactivity, on βAR-dependent alterations in cardiomyocyte Ca2+ handling and hypertrophy. Methods and Results:Using transgenic mice to titrate the levels of protein S-Nitrosylation, we uncovered major roles for protein S-Nitrosylation, in general, and for phospholamban and cardiac troponin C S-Nitrosylation, in particular, in βAR-dependent re...
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protein microarray characterization of the s nitrosoproteome
Molecular & Cellular Proteomics, 2014Co-Authors: Yun Il Lee, Paschalis-Thomas Doulias, Daniel Giovinazzo, Ho Chul Kang, Yunjong Lee, Jun Seop Jeong, Zhi Xie, Mehdi Ghasemi, Harry IschiropoulosAbstract:Nitric oxide (NO) mediates a substantial part of its physiologic functions via S-Nitrosylation, however the cellular substrates for NO-mediated S-Nitrosylation are largely unknown. Here we describe the S-nitrosoproteome using a high-density protein microarray chip containing 16,368 unique human proteins. We identified 834 potentially S-nitrosylated human proteins. Using a unique and highly specific labeling and affinity capture of S-nitrosylated proteins, 138 cysteine residues on 131 peptides in 95 proteins were determined, defining critical sites of NO's actions. Of these cysteine residues 113 are novel sites of S-Nitrosylation. A consensus sequence motif from these 834 proteins for S-Nitrosylation was identified, suggesting that the residues flanking the S-nitrosylated cysteine are likely to be the critical determinant of whether the cysteine is S-nitrosylated. We identify eight ubiquitin E3 ligases, RNF10, RNF11, RNF41, RNF141, RNF181, RNF208, WWP2, and UBE3A, whose activities are modulated by S-Nitrosylation, providing a unique regulatory mechanism of the ubiquitin proteasome system. These results define a new and extensive set of proteins that are susceptible to NO regulation via S-Nitrosylation. Similar approaches could be used to identify other post-translational modification proteomes.
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regulation of protein function and signaling by reversible cysteine s nitrosylation
Journal of Biological Chemistry, 2013Co-Authors: Neal S Gould, Paschalis-Thomas Doulias, Margarita Tenopoulou, Karthik Raju, Harry IschiropoulosAbstract:NO is a versatile free radical that mediates numerous biological functions within every major organ system. A molecular pathway by which NO accomplishes functional diversity is the selective modification of protein cysteine residues to form S-nitrosocysteine. This post-translational modification, S-Nitrosylation, impacts protein function, stability, and location. Despite considerable advances with individual proteins, the in vivo biological chemistry, the structural elements that govern the selective S-Nitrosylation of cysteine residues, and the potential overlap with other redox modifications are unknown. In this minireview, we explore the functional features of S-Nitrosylation at the proteome level and the structural diversity of endogenously modified residues, and we discuss the potential overlap and complementation that may exist with other cysteine modifications.
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nitric oxide regulates mitochondrial fatty acid metabolism through reversible protein s nitrosylation
Science Signaling, 2013Co-Authors: Paschalis-Thomas Doulias, Margarita Tenopoulou, Jennifer L Greene, Karthik Raju, Harry IschiropoulosAbstract:Cysteine S-Nitrosylation is a posttranslational modification by which nitric oxide regulates protein function and signaling. Studies of individual proteins have elucidated specific functional roles for S-Nitrosylation, but knowledge of the extent of endogenous S-Nitrosylation, the sites that are nitrosylated, and the regulatory consequences of S-Nitrosylation remains limited. We used mass spectrometry-based methodologies to identify 1011 S-nitrosocysteine residues in 647 proteins in various mouse tissues. We uncovered selective S-Nitrosylation of enzymes participating in glycolysis, gluconeogenesis, tricarboxylic acid cycle, and oxidative phosphorylation, indicating that this posttranslational modification may regulate metabolism and mitochondrial bioenergetics. S-Nitrosylation of the liver enzyme VLCAD [very long chain acyl-coenzyme A (CoA) dehydrogenase] at Cys(238), which was absent in mice lacking endothelial nitric oxide synthase, improved its catalytic efficiency. These data implicate protein S-Nitrosylation in the regulation of β-oxidation of fatty acids in mitochondria.
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lymphocyte development requires s nitrosoglutathione reductase
Journal of Immunology, 2010Co-Authors: Zhiyong Yang, Zhien Wang, Paschalis-Thomas Doulias, Harry Ischiropoulos, Richard M LocksleyAbstract:NO is critical to immunity, but its role in the development of the immune system is unknown. In this study, we show that S-nitrosoglutathione reductase (GSNOR), a protein key to the control of protein S-Nitrosylation, is important for the development of lymphocytes. Genetic deletion of GSNOR in mice results in significant decrease in both T and B lymphocytes in the periphery. In thymus, GSNOR deficiency causes excessive protein S-Nitrosylation, increases apoptosis, and reduces the number of CD4 single-positive thymocytes. Lymphopenia and increase in S-Nitrosylation and apoptosis in GSNOR-deficient mice are largely abolished by genetic deletion of inducible NO synthase. Furthermore, the protection of lymphocyte development by GSNOR is apparently intrinsic to hematopoietic cells. Thus, GSNOR, likely through regulation of S-Nitrosylation and apoptosis, physiologically plays a protective role in the development of the immune system.
Douglas T. Hess - One of the best experts on this subject based on the ideXlab platform.
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s nitrosylation of β arrestins biases receptor signaling and confers ligand independence
Molecular Cell, 2018Co-Authors: Hiroki Hayashi, Douglas T. Hess, Rongli Zhang, Keiki Sugi, Huiyun Gao, Bea L Tan, Dawn E Bowles, Carmelo A Milano, Mukesh K Jain, Walter J KochAbstract:Summary Most G protein-coupled receptors (GPCRs) signal through both heterotrimeric G proteins and β-arrestins (βarr1 and βarr2). Although synthetic ligands can elicit biased signaling by G protein- vis-a-vis βarr-mediated transduction, endogenous mechanisms for biasing signaling remain elusive. Here we report that S-Nitrosylation of a novel site within βarr1/2 provides a general mechanism to bias ligand-induced signaling through GPCRs by selectively inhibiting βarr-mediated transduction. Concomitantly, S-Nitrosylation endows cytosolic βarrs with receptor-independent function. Enhanced βarr S-Nitrosylation characterizes inflammation and aging as well as human and murine heart failure. In genetically engineered mice lacking βarr2-Cys253 S-Nitrosylation, heart failure is exacerbated in association with greatly compromised β-adrenergic chronotropy and inotropy, reflecting βarr-biased transduction and β-adrenergic receptor downregulation. Thus, S-Nitrosylation regulates βarr function and, thereby, biases transduction through GPCRs, demonstrating a novel role for nitric oxide in cellular signaling with potentially broad implications for patho/physiological GPCR function, including a previously unrecognized role in heart failure.
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A Multiplex Enzymatic Machinery for Cellular Protein S-Nitrosylation
Molecular Cell, 2018Co-Authors: Divya Seth, Alfred Hausladen, Yajuan Wang, Douglas T. Hess, Liwen Wang, Jonathan S StamlerAbstract:Summary S-Nitrosylation, the oxidative modification of Cys residues by nitric oxide (NO) to form S-nitrosothiols (SNOs), modifies all main classes of proteins and provides a fundamental redox-based cellular signaling mechanism. However, in contrast to other post-translational protein modifications, S-Nitrosylation is generally considered to be non-enzymatic, involving multiple chemical routes. We report here that endogenous protein S-Nitrosylation in the model organism E. coli depends principally upon the enzymatic activity of the hybrid cluster protein Hcp, employing NO produced by nitrate reductase. Anaerobiosis on nitrate induces both Hcp and nitrate reductase, thereby resulting in the S-Nitrosylation-dependent assembly of a large interactome including enzymes that generate NO (NO synthase), synthesize SNO-proteins (SNO synthase), and propagate SNO-based signaling (trans-nitrosylases) to regulate cell motility and metabolism. Thus, protein S-Nitrosylation by NO in E. coli is essentially enzymatic, and the potential generality of the multiplex enzymatic mechanism that we describe may support a re-conceptualization of NO-based cellular signaling.
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protein s nitrosylation determinants of specificity and enzymatic regulation of s nitrosothiol based signaling
Antioxidants & Redox Signaling, 2018Co-Authors: Colin T. Stomberski, Jonathan S Stamler, Douglas T. HessAbstract:Abstract Significance: Protein S-Nitrosylation, the oxidative modification of cysteine by nitric oxide (NO) to form protein S-nitrosothiols (SNOs), mediates redox-based signaling that conveys, in large part, the ubiquitous influence of NO on cellular function. S-Nitrosylation regulates protein activity, stability, localization, and protein–protein interactions across myriad physiological processes, and aberrant S-Nitrosylation is associated with diverse pathophysiologies. Recent Advances: It is recently recognized that S-Nitrosylation endows S-nitroso-protein (SNO-proteins) with S-nitrosylase activity, that is, the potential to trans-S-nitrosylate additional proteins, thereby propagating SNO-based signals, analogous to kinase-mediated signaling cascades. In addition, it is increasingly appreciated that cellular S-Nitrosylation is governed by dynamically coupled equilibria between SNO-proteins and low-molecular-weight SNOs, which are controlled by a growing set of enzymatic denitrosylases comprising two ma...
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Identification of S-nitroso-CoA reductases that regulate protein S-Nitrosylation.
Proceedings of the National Academy of Sciences of the United States of America, 2014Co-Authors: Puneet Anand, Alfred Hausladen, Yajuan Wang, Guofang Zhang, Colin T. Stomberski, Henri Brunengraber, Douglas T. Hess, Jonathan S StamlerAbstract:Coenzyme A (CoA) mediates thiol-based acyl-group transfer (acetylation and palmitoylation). However, a role for CoA in the thiol-based transfer of NO groups (S-Nitrosylation) has not been considered. Here we describe protein S-Nitrosylation in yeast (heretofore unknown) that is mediated by S-nitroso-CoA (SNO-CoA). We identify a specific SNO-CoA reductase encoded by the alcoholdehydrogenase 6 (ADH6) gene and show that deletion of ADH6 increases cellular S-Nitrosylation and alters CoA metabolism. Further, we report that Adh6, acting as a selective SNO-CoA reductase, protects acetoacetyl–CoA thiolase from inhibitory S-Nitrosylation and thereby affects sterol biosynthesis. Thus, Adh6-regulated, SNO-CoA–mediated protein S-Nitrosylation provides a regulatory mechanism paralleling protein acetylation. We also find that SNO-CoA reductases are present from bacteria to mammals, and we identify aldo-keto reductase 1A1 as the mammalian functional analog of Adh6. Our studies reveal a novel functional class of enzymes that regulate protein S-Nitrosylation from yeast to mammals and suggest that SNO-CoA–mediated S-Nitrosylation may subserve metabolic regulation.
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regulation by s nitrosylation of protein post translational modification
Journal of Biological Chemistry, 2012Co-Authors: Douglas T. Hess, Jonathan S StamlerAbstract:Abstract Protein post-translational modification by S-Nitrosylation conveys a ubiquitous influence of nitric oxide on signal transduction in eukaryotic cells. The wide functional purview of S-Nitrosylation reflects in part the regulation by S-Nitrosylation of the principal protein post-translational modifications that play a role in cell signaling, including phosphorylation, acetylation, ubiquitylation and related modifications, palmitoylation, and alternative Cys-based redox modifications. In this minireview, we discuss the mechanisms through which S-Nitrosylation exerts its broad pleiotropic influence on protein post-translational modification.
Satoru Kato - One of the best experts on this subject based on the ideXlab platform.
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neuritogenic activity of a genipin derivative in retinal ganglion cells is mediated by retinoic acid receptor β expression through nitric oxide s nitrosylation signaling
Journal of Neurochemistry, 2011Co-Authors: Yoshiki Koriyama, Yusuke Takagi, Kenzo Chiba, Matsumi Yamazaki, Kunizo Arai, Toru Matsukawa, Hirokazu Suzuki, Kayo Sugitani, Hiroyuki Kagechika, Satoru KatoAbstract:J. Neurochem. (2011) 10.1111/j.1471-4159.2011.07533.x Abstract Genipin, a herbal iridoid, is known to have both neuroprotective and neuritogenic activity in neuronal cell lines. As it is structurally similar to tetrahydrobiopterin, its activity is believed to be nitric oxide (NO)-dependent. We previously proposed a novel neuroprotective activity of a genipin derivative, (1R)-isoPropyloxygenipin (IPRG001), whereby it reduces oxidative stress in RGC-5, a neuronal precursor cell line of retinal origin through protein S-Nitrosylation. In the present study, we investigated another neuritogenic property of IPRG001 in RGC-5 cells and retinal explant culture where in we focused on the NO-cGMP-dependent and protein S-Nitrosylation pathways. IPRG001 stimulated neurite outgrowth in RGC-5 cells and retinal explant culture through NO-dependent signaling, but not NO-dependent cGMP signaling. Neurite outgrowth with IPRG001 requires retinoic acid receptor β (RARβ) expression, which is suppressed by an RAR blocking agent and siRNA inhibition. Thereby, we hypothesized that RARβ expression is mediated by protein S-Nitrosylation. S-Nitrosylation of histone deacetylase 2 is a key mechanism in chromatin remodeling leading to transcriptional gene activation. We found a parallelism between S-Nitrosylation of histone diacetylase 2 and the induction of RARβ expression with IPRG001 treatment. The both neuroprotective and neuritogenic activities of genipin could be a new target for the regeneration of retinal ganglion cells after glaucomatous conditions.
