scholarly journals Redox Regulation by Protein S-Glutathionylation: From Molecular Mechanisms to Implications in Health and Disease

2020 ◽  
Vol 21 (21) ◽  
pp. 8113 ◽  
Author(s):  
Aysenur Musaogullari ◽  
Yuh-Cherng Chai
Keyword(s):  
Protein Function ◽  
Liver Diseases ◽  
Redox Regulation ◽  
Molecular Mechanisms ◽  
Protein S ◽  
Protective Mechanism ◽  
Post Translational Modification ◽  
Physiological Processes ◽  
Health And Disease ◽  
Mixed Disulfides

S-glutathionylation, the post-translational modification forming mixed disulfides between protein reactive thiols and glutathione, regulates redox-based signaling events in the cell and serves as a protective mechanism against oxidative damage. S-glutathionylation alters protein function, interactions, and localization across physiological processes, and its aberrant function is implicated in various human diseases. In this review, we discuss the current understanding of the molecular mechanisms of S-glutathionylation and describe the changing levels of expression of S-glutathionylation in the context of aging, cancer, cardiovascular, and liver diseases.

PGluS: prediction of protein S-glutathionylation sites with multiple features and analysis

2015 ◽  
Vol 11 (3) ◽  
pp. 923-929 ◽  
Author(s):  
Xiaowei Zhao ◽  
Qiao Ning ◽  
Meiyu Ai ◽  
Haiting Chai ◽  
Minghao Yin
Keyword(s):  
Protein Stability ◽  
Redox Regulation ◽  
Protein S ◽  
Cysteine Residues ◽  
Post Translational Modification ◽  
Multiple Features ◽  
Mixed Disulfides

S-Glutathionylation is a reversible protein post-translational modification, which generates mixed disulfides between glutathione (GSH) and cysteine residues, playing an important role in regulating protein stability, activity, and redox regulation.

scholarly journals Protein S-nitrosation differentially modulates tomato responses to infection by hemi-biotrophic oomycetes of Phytophthora spp.

2021 ◽  
Vol 8 (1) ◽  
Author(s):  
Tereza Jedelská ◽  
Michaela Sedlářová ◽  
Jan Lochman ◽  
Lucie Činčalová ◽  
Lenka Luhová ◽  
...  
Keyword(s):  
Stress Responses ◽  
Protein Level ◽  
Protein Function ◽  
Molecular Mechanisms ◽  
Reductase Activity ◽  
Protein S ◽  
Post Inoculation ◽  
Vascular Bundles ◽  
Post Translational Modification ◽  
Defence Proteins

AbstractRegulation of protein function by reversible S-nitrosation, a post-translational modification based on the attachment of nitroso group to cysteine thiols, has emerged among key mechanisms of NO signalling in plant development and stress responses. S-nitrosoglutathione is regarded as the most abundant low-molecular-weight S-nitrosothiol in plants, where its intracellular concentrations are modulated by S-nitrosoglutathione reductase. We analysed modulations of S-nitrosothiols and protein S-nitrosation mediated by S-nitrosoglutathione reductase in cultivated Solanum lycopersicum (susceptible) and wild Solanum habrochaites (resistant genotype) up to 96 h post inoculation (hpi) by two hemibiotrophic oomycetes, Phytophthora infestans and Phytophthora parasitica. S-nitrosoglutathione reductase activity and protein level were decreased by P. infestans and P. parasitica infection in both genotypes, whereas protein S-nitrosothiols were increased by P. infestans infection, particularly at 72 hpi related to pathogen biotrophy–necrotrophy transition. Increased levels of S-nitrosothiols localised in both proximal and distal parts to the infection site, which suggests together with their localisation to vascular bundles a signalling role in systemic responses. S-nitrosation targets in plants infected with P. infestans identified by a proteomic analysis include namely antioxidant and defence proteins, together with important proteins of metabolic, regulatory and structural functions. Ascorbate peroxidase S-nitrosation was observed in both genotypes in parallel to increased enzyme activity and protein level during P. infestans pathogenesis, namely in the susceptible genotype. These results show important regulatory functions of protein S-nitrosation in concerting molecular mechanisms of plant resistance to hemibiotrophic pathogens.

Abstract 15523: Dynamic Protein S-palmitoylation Contributes to Cardiac Remodeling During Aging With Chronic Hypertension

Circulation ◽  
2020 ◽  
Vol 142 (Suppl_3) ◽  
Author(s):  
Madeleine R Miles ◽  
John Seo ◽  
Zachary Wilson ◽  
Min Jiang ◽  
Gea-ny Tseng
Keyword(s):  
Heart Failure ◽  
Protein Function ◽  
Ventricular Myocytes ◽  
Wide Spectrum ◽  
Enrichment Analysis ◽  
Protein S ◽  
Ventricular Myocardium ◽  
Chronic Hypertension ◽  
Post Translational Modification ◽  
Α Subunit

Introduction: More that 10% of human proteins can be S-palmitoylated, a post-translational modification (PTM) whereby palmitoyl chains are covalently linked to cysteine thiol groups. S-palmitoylation influences protein trafficking, distribution and function. There is no information on the scope of protein S-palmitoylation in the heart, or how this enzyme-mediated reversible PTM is regulated. Hypothesis: S-palmitoylation occurs to a wide spectrum of proteins in cardiomyocytes, and is coordinated by membrane-embedded palmitoylating (DHHC) enzymes. DHHC enzymes are subject to remodeling during chronic hypertension. Methods: We used resin-assisted capture to purify S-palmitoylated proteins from ventricular myocardium of 3 species: human, dog, and rat. We used global unbiased proteomic search to identify S-palmitoylated proteins. We validated DHHC antibodies and used them to monitor protein level and subcellular distribution of native DHHC enzymes in ventricular myocytes. Results: We built a 'composite' cardiac palmitome composed of 462 S-palmitoylatable proteins identified in ≥ 2 species-specific cardiac palmitomes. Enrichment analysis based on GO term 'cellular component' indicated that they are mainly involved in cell-cell and cell-substrate associations, sarcolemma and sarcomere organization, vesicular trafficking, G-protein function, ATP-dependent transmembrane transport, and mitochondria inner and outer membrane organization. Among the 23 DHHC enzymes, we detected ten in hearts across species. In ventricular myocytes with well-defined subcellular compartments, DHHC enzymes exhibited distinct distribution patterns: peripheral sarcolemma (DHHC1), M-lines (DHHC2), Z-lines (DHHC5), vesicles (DHHC7) and intercalated disc (DHHC9). In aging spontaneously hypertensive rats (a model of chronic hypertension, some in heart failure), seven DHHC enzymes were upregulated in the heart, accompanied by a higher degree of S-palmitoylation of CaMK II, caveolin3, Na/Ca exchanger, and Na/K pump α-subunit. Conclusion: S-palmitoylation is involved in most, if not all, aspects of cardiomyocyte function. Palmitoylation dysregulation may contribute to pathological progression in hypertrophy leading to heart failure.

scholarly journals Redox Regulation of T-Cell Function: From Molecular Mechanisms to Significance in Human Health and Disease

2013 ◽  
Vol 18 (12) ◽  
pp. 1497-1534 ◽  
Author(s):  
Pravin Kesarwani ◽  
Anuradha K. Murali ◽  
Amir A. Al-Khami ◽  
Shikhar Mehrotra
Keyword(s):  
T Cell ◽  
Human Health ◽  
Redox Regulation ◽  
Molecular Mechanisms ◽  
Cell Function ◽  
T Cell Function ◽  
Health And Disease

scholarly journals Therapeutic Potential of Targeting the SUMO Pathway in Cancer

Cancers ◽  
2021 ◽  
Vol 13 (17) ◽  
pp. 4402
Author(s):  
Antti Kukkula ◽  
Veera K. Ojala ◽  
Lourdes M. Mendez ◽  
Lea Sistonen ◽  
Klaus Elenius ◽  
...  
Keyword(s):  
Tumor Suppressors ◽  
Protein Function ◽  
Molecular Mechanisms ◽  
Therapeutic Potential ◽  
Dependent Manner ◽  
Post Translational Modification ◽  
Recent Developments ◽  
Sumo Pathway ◽  
Multiple Levels

SUMOylation is a dynamic and reversible post-translational modification, characterized more than 20 years ago, that regulates protein function at multiple levels. Key oncoproteins and tumor suppressors are SUMO substrates. In addition to alterations in SUMO pathway activity due to conditions typically present in cancer, such as hypoxia, the SUMO machinery components are deregulated at the genomic level in cancer. The delicate balance between SUMOylation and deSUMOylation is regulated by SENP enzymes possessing SUMO-deconjugation activity. Dysregulation of SUMO machinery components can disrupt the balance of SUMOylation, contributing to the tumorigenesis and drug resistance of various cancers in a context-dependent manner. Many molecular mechanisms relevant to the pathogenesis of specific cancers involve SUMO, highlighting the potential relevance of SUMO machinery components as therapeutic targets. Recent advances in the development of inhibitors targeting SUMOylation and deSUMOylation permit evaluation of the therapeutic potential of targeting the SUMO pathway in cancer. Finally, the first drug inhibiting SUMO pathway, TAK-981, is currently also being evaluated in clinical trials in cancer patients. Intriguingly, the inhibition of SUMOylation may also have the potential to activate the anti-tumor immune response. Here, we comprehensively and systematically review the recent developments in understanding the role of SUMOylation in cancer and specifically focus on elaborating the scientific rationale of targeting the SUMO pathway in different cancers.

scholarly journals The Gut-Liver Axis in Health and Disease: The Role of Gut Microbiota-Derived Signals in Liver Injury and Regeneration

2021 ◽  
Vol 12 ◽  
Author(s):  
Zhipeng Zheng ◽  
Baohong Wang
Keyword(s):  
Liver Injury ◽  
Gut Microbiota ◽  
Liver Regeneration ◽  
Liver Diseases ◽  
Molecular Mechanisms ◽  
Short Chain Fatty Acids ◽  
Pathophysiological Process ◽  
Tryptophan Metabolites ◽  
Health And Disease

Diverse liver diseases undergo a similar pathophysiological process in which liver regeneration follows a liver injury. Given the important role of the gut-liver axis in health and diseases, the role of gut microbiota-derived signals in liver injury and regeneration has attracted much attention. It has been observed that the composition of gut microbiota dynamically changes in the process of liver regeneration after partial hepatectomy, and gut microbiota modulation by antibiotics or probiotics affects both liver injury and regeneration. Mechanically, through the portal vein, the liver is constantly exposed to gut microbial components and metabolites, which have immense effects on the immunity and metabolism of the host. Emerging data demonstrate that gut-derived lipopolysaccharide, gut microbiota-associated bile acids, and other bacterial metabolites, such as short-chain fatty acids and tryptophan metabolites, may play multifaceted roles in liver injury and regeneration. In this perspective, we provide an overview of the possible molecular mechanisms by which gut microbiota-derived signals modulate liver injury and regeneration, highlighting the potential roles of gut microbiota in the development of gut microbiota-based therapies to alleviate liver injury and promote liver regeneration.

Abstract 223: S-glutathiolation Uncouples Endothelial Nitric Oxide (NO) Synthase, Switching Enzyme from NO to Superoxide Production

Circulation ◽  
2008 ◽  
Vol 118 (suppl_18) ◽  
Author(s):  
Chun-An Chen ◽  
Lawrence J Druhan ◽  
Tse-Yao Wang ◽  
Yeong-Renn Chen ◽  
Jay L Zweier
Keyword(s):  
Oxidative Stress ◽  
Protein Modification ◽  
Redox Regulation ◽  
Cardiovascular Function ◽  
Heart Association ◽  
Protein S ◽  
No Production ◽  
Protein Thiols ◽  
Mixed Disulfides ◽  
Endothelial Nitric Oxide

Overproduction of superoxide (•O 2 − ) and •O 2 − -derived oxidants increases cellular oxidative stress. This can lead to cell death, via apoptosis or necrosis. An important response of protein thiols to oxidative stress is reversible formation of protein mixed disulfides via S-glutathiolation. This redox based protein modification is thought to play an important role as an adaptive response to oxidative injury in cells, or alternatively in controlling cellular signaling in a manner similar to phosphorylation. Protein S-glutathiolation is increased in the post-ischemic heart. Human eNOS, which is of critical importance in maintaining cardiovascular function, contains 29 cysteinyl residues. To investigate the effects of S-glutathiolation on the regulation of eNOS function and its relation to cardiovascular diseases, eNOS functional alterations induced by S-glutathiolation were studied. Additionally, LC/MS/MS was used to determine the precise residues of eNOS involved in this redox-dependent thiol modification. S-glutatiolation significantly reduced NO production from heNOS, with a 63% decrease induced by incubation with 2 mM GSSG in vitro . This process was reversible by addition of DTT. Alkylation of the cysteinyl residues with N-ethylmaleimide (NEM) completely inhibited NO production. S-glutathiolation of an uncoupled heNOS increased •O 2 − generation (> 70%), and this increase was only partially blocked by L-NAME, implicating the reductase site as the source for the increased •O 2 − generation. When the cysteinyl residues were all alkylated with NEM, the •O 2 − generation from eNOS was dramatically increased (+2.4-fold), and this increase was not inhibited by L-NAME. We have identified three cysteine residues, C 382 , C 689 and C 908 as sights of S-glutathiolation in heNOS, all three of which are conserved in all known mammalian eNOS enzymes. Therefore, cysteinyl residues are critical for the regulation of eNOS coupling, and S-glutatiolation of specific residues switches eNOS from an NO producing to a •O 2 − generating enzyme, by inducing electron leakage from the reductase domain. As such, S-glutathiolation provides a novel mechanism for the regulation of heNOS, defining a unique pathway for the redox regulation of cardiovascular function. This research has received full or partial funding support from the American Heart Association, AHA Great Rivers Affiliate (Delaware, Kentucky, Ohio, Pennsylvania & West Virginia).

H2S signaling in redox regulation of cellular functions

2013 ◽  
Vol 91 (1) ◽  
pp. 8-14 ◽  
Author(s):  
Youngjun Ju ◽  
Weihua Zhang ◽  
Yanxi Pei ◽  
Guangdong Yang
Keyword(s):  
Mammalian Cells ◽  
Redox Regulation ◽  
Molecular Mechanisms ◽  
Current Knowledge ◽  
Redox Homeostasis ◽  
Therapeutic Interventions ◽  
Post Translational Modification ◽  
Cellular Functions ◽  
Future Design ◽  
Cellular Effects

Hydrogen sulfide (H2S) is traditionally recognized as a toxic gas with a rotten-egg smell. In just the last few decades, H2S has been found to be one of a family of gasotransmitters, together with nitric oxide and carbon monoxide, and various physiologic effects of H2S have been reported. Among the most acknowledged molecular mechanisms for the cellular effects of H2S is the regulation of intracellular redox homeostasis and post-translational modification of proteins through S-sulfhydration. On the one side, H2S can promote an antioxidant effect and is cytoprotective; on the other side, H2S stimulates oxidative stress and is cytotoxic. This review summarizes our current knowledge of the antioxidant versus pro-oxidant effects of H2S in mammalian cells and describes the Janus-faced properties of this novel gasotransmitter. The redox regulation for the cellular effects of H2S through S-sulfhydration and the role of H2S in glutathione generation is also recapitulated. A better understanding of H2S-regualted redox homeostasis will pave the way for future design of novel pharmacological and therapeutic interventions for various diseases.

scholarly journals MetOSite: an integrated resource for the study of methionine residues sulfoxidation

2019 ◽  
Vol 35 (22) ◽  
pp. 4849-4850 ◽  
Author(s):  
Héctor Valverde ◽  
Francisco R Cantón ◽  
Juan Carlos Aledo
Keyword(s):  
Protein Interaction ◽  
Protein Function ◽  
Redox Regulation ◽  
Homo Sapiens ◽  
Methionine Sulfoxide ◽  
Subcellular Location ◽  
Biological Properties ◽  
Post Translational Modification ◽  
Protein Protein Interaction ◽  
Methionine Residues

Abstract Motivation The oxidation of protein-bound methionine to form methionine sulfoxide has traditionally been regarded as an oxidative damage. However, growing evidences support the view of this reversible reaction also as a regulatory post-translational modification. Thus, the oxidation of methionine residues has been reported to have multiple and varied implications for protein function. However, despite the importance of this modification and the abundance of reports, all these data are scattered in the literature. No database/resource on methionine sulfoxidation exists currently. Since this information is useful to gain further insights into the redox regulation of cellular proteins, we have created a primary database of experimentally confirmed sulfoxidation sites. Results MetOSite currently contains 7242 methionine sulfoxide sites found in 3562 different proteins from 23 species, with Homo sapiens, Arabidopsis thaliana and Bacillus cereus as the main contributors. Each collected site has been classified according to the effect of its sulfoxidation on the biological properties of the modified protein. Thus, MetOSite documents cases where the sulfoxidation of methionine leads to (i) gain of activity, (ii) loss of activity, (iii) increased protein–protein interaction susceptibility, (iv) decreased protein–protein interaction susceptibility, (v) changes in protein stability and (vi) changes in subcellular location. Availability and implementation MetOSite is available at https://metosite.uma.es.

scholarly journals Role of Glutathionylation in Infection and Inflammation

Nutrients ◽  
2019 ◽  
Vol 11 (8) ◽  
pp. 1952 ◽  
Author(s):  
Paola Checconi ◽  
Dolores Limongi ◽  
Sara Baldelli ◽  
Maria Rosa Ciriolo ◽  
Lucia Nencioni ◽  
...  
Keyword(s):  
Protein Function ◽  
Host Response ◽  
Redox State ◽  
Cellular Proteins ◽  
Host Responses ◽  
Post Translational Modification ◽  
Microbial Infections ◽  
Infection And Inflammation ◽  
Mixed Disulfides

Glutathionylation, that is, the formation of mixed disulfides between protein cysteines and glutathione (GSH) cysteines, is a reversible post-translational modification catalyzed by different cellular oxidoreductases, by which the redox state of the cell modulates protein function. So far, most studies on the identification of glutathionylated proteins have focused on cellular proteins, including proteins involved in host response to infection, but there is a growing number of reports showing that microbial proteins also undergo glutathionylation, with modification of their characteristics and functions. In the present review, we highlight the signaling role of GSH through glutathionylation, particularly focusing on microbial (viral and bacterial) glutathionylated proteins (GSSPs) and host GSSPs involved in the immune/inflammatory response to infection; moreover, we discuss the biological role of the process in microbial infections and related host responses.

Sign in / Sign up

Export Citation Format

Share Document