scholarly journals Signals Getting Crossed in the Entanglement of Redox and Phosphorylation Pathways: Phosphorylation of Peroxiredoxin Proteins Sparks Cell Signaling

Antioxidants ◽  
2019 ◽  
Vol 8 (2) ◽  
pp. 29 ◽  
Author(s):  
John Skoko ◽  
Shireen Attaran ◽  
Carola Neumann
Keyword(s):  
Cell Signaling ◽  
Cell Fate ◽  
Intracellular Signaling ◽  
Redox Homeostasis ◽  
Three Dimensional ◽  
Cysteine Residue ◽  
Signaling Cascades ◽  
Dimensional Structure ◽  
Post Translational Modification ◽  
Downstream Signaling

Reactive oxygen and nitrogen species have cell signaling properties and are involved in a multitude of processes beyond redox homeostasis. The peroxiredoxin (Prdx) proteins are highly sensitive intracellular peroxidases that can coordinate cell signaling via direct reactive species scavenging or by acting as a redox sensor that enables control of binding partner activity. Oxidation of the peroxidatic cysteine residue of Prdx proteins are the classical post-translational modification that has been recognized to modulate downstream signaling cascades, but increasing evidence supports that dynamic changes to phosphorylation of Prdx proteins is also an important determinant in redox signaling. Phosphorylation of Prdx proteins affects three-dimensional structure and function to coordinate cell proliferation, wound healing, cell fate and lipid signaling. The advent of large proteomic datasets has shown that there are many opportunities to understand further how phosphorylation of Prdx proteins fit into intracellular signaling cascades in normal or malignant cells and that more research is necessary. This review summarizes the Prdx family of proteins and details how post-translational modification by kinases and phosphatases controls intracellular signaling.

scholarly journals Mitochondria as intracellular signaling platforms in health and disease

2020 ◽  
Vol 219 (5) ◽  
Author(s):  
Jay X. Tan ◽  
Toren Finkel
Keyword(s):  
Cell Fate ◽  
Intracellular Signaling ◽  
Redox Homeostasis ◽  
Innate Immune ◽  
Signaling Cascades ◽  
Cell Fate Determination ◽  
Age Related ◽  
Mitochondrial Signaling ◽  
Health And Disease ◽  
Multiple Signaling

Mitochondria, long viewed solely in the context of bioenergetics, are increasingly emerging as critical hubs for intracellular signaling. Due to their bacterial origin, mitochondria possess their own genome and carry unique lipid components that endow these organelles with specialized properties to help orchestrate multiple signaling cascades. Mitochondrial signaling modulates diverse pathways ranging from metabolism to redox homeostasis to cell fate determination. Here, we review recent progress in our understanding of how mitochondria serve as intracellular signaling platforms with a particular emphasis on lipid-mediated signaling, innate immune activation, and retrograde signaling. We further discuss how these signaling properties might potentially be exploited to develop new therapeutic strategies for a range of age-related conditions.

scholarly journals Roles of sphingosine-1-phosphate signaling in cancer

2019 ◽  
Vol 19 (1) ◽  
Author(s):  
Peng Wang ◽  
Yonghui Yuan ◽  
Wenda Lin ◽  
Hongshan Zhong ◽  
Ke Xu ◽  
...  
Keyword(s):  
Cell Fate ◽  
Cancer Progression ◽  
Therapeutic Potential ◽  
Receptor Activation ◽  
Signaling Cascades ◽  
Lipid Mediator ◽  
Downstream Signaling ◽  
Sphingosine 1 Phosphate ◽  
Sphingosine Kinases ◽  
And Migration

AbstractThe potent pleiotropic lipid mediator sphingosine-1-phosphate (S1P) participates in numerous cellular processes, including angiogenesis and cell survival, proliferation, and migration. It is formed by one of two sphingosine kinases (SphKs), SphK1 and SphK2. These enzymes largely exert their various biological and pathophysiological actions through one of five G protein-coupled receptors (S1PR1–5), with receptor activation setting in motion various signaling cascades. Considerable evidence has been accumulated on S1P signaling and its pathogenic roles in diseases, as well as on novel modulators of S1P signaling, such as SphK inhibitors and S1P agonists and antagonists. S1P and ceramide, composed of sphingosine and a fatty acid, are reciprocal cell fate regulators, and S1P signaling plays essential roles in several diseases, including inflammation, cancer, and autoimmune disorders. Thus, targeting of S1P signaling may be one way to block the pathogenesis and may be a therapeutic target in these conditions. Increasingly strong evidence indicates a role for the S1P signaling pathway in the progression of cancer and its effects. In the present review, we discuss recent progress in our understanding of S1P and its related proteins in cancer progression. Also described is the therapeutic potential of S1P receptors and their downstream signaling cascades as targets for cancer treatment.

scholarly journals Enhancing autophagy by redox regulation extends lifespan in Drosophila

2019 ◽  
Author(s):  
Helena M. Cochemé ◽  
Ivana Bjedov ◽  
Sebastian Grönke ◽  
Katja E. Menger ◽  
Andrew M. James ◽  
...  
Keyword(s):  
Redox Regulation ◽  
Redox Homeostasis ◽  
Model Organism ◽  
Fruit Fly ◽  
Cysteine Residue ◽  
Lifespan Extension ◽  
Post Translational Modification ◽  
Redox Signalling ◽  
Age Related

Redox signalling is an important modulator of diverse biological pathways and processes, and operates through specific post-translational modification of redox-sensitive thiols on cysteine residues 1–4. Critically, redox signalling is distinct from irreversible oxidative damage and functions as a reversible ‘redox switch’ to regulate target proteins. H2O2 acts as the major effector of redox signalling, both directly and through intracellular thiol redox relays 5,6. Dysregulation of redox homeostasis has long been implicated in the pathophysiology of many age-related diseases, as well as in the ageing process itself, however the underlying mechanisms remain largely unclear 7,8. To study redox signalling by H2O2in vivo and explore its involvement in metabolic health and longevity, we used the fruit fly Drosophila as a model organism, with its tractable lifespan and strong evolutionary conservation with mammals 9. Here we report that inducing an endogenous redox-shift, by manipulating levels of the H2O2-degrading enzyme catalase, improves health and robustly extends lifespan in flies, independently of oxidative stress resistance and dietary restriction. We find that the catalase redox-shifted flies are acutely sensitive to starvation stress, which relies on autophagy as a vital survival mechanism. Importantly, we show that autophagy is essential for the lifespan extension of the catalase flies. Furthermore, using redox-inactive knock-in mutants of Atg4a, a major effector of autophagy, we show that the lifespan extension in response to catalase requires a key redox-regulatory cysteine residue, Cys102 in Atg4a. These findings demonstrate that redox regulation of autophagy can extend lifespan, confirming the importance of redox signalling in ageing and as a potential pro-longevity target.

scholarly journals TAK1 kinase switches cell fate from apoptosis to necrosis following TNF stimulation

2014 ◽  
Vol 204 (4) ◽  
pp. 607-623 ◽  
Author(s):  
Sho Morioka ◽  
Peter Broglie ◽  
Emily Omori ◽  
Yuka Ikeda ◽  
Giichi Takaesu ◽  
...  
Keyword(s):  
Cell Fate ◽  
Intracellular Signaling ◽  
Signaling Cascades ◽  
Caspase 8 ◽  
Interacting Protein ◽  
Cellular Context ◽  
Biological Event ◽  
Apoptosis And Necrosis

TNF activates three distinct intracellular signaling cascades leading to cell survival, caspase-8–mediated apoptosis, or receptor interacting protein kinase 3 (RIPK3)–dependent necrosis, also called necroptosis. Depending on the cellular context, one of these pathways is activated upon TNF challenge. When caspase-8 is activated, it drives the apoptosis cascade and blocks RIPK3-dependent necrosis. Here we report the biological event switching to activate necrosis over apoptosis. TAK1 kinase is normally transiently activated upon TNF stimulation. We found that prolonged and hyperactivation of TAK1 induced phosphorylation and activation of RIPK3, leading to necrosis without caspase activation. In addition, we also demonstrated that activation of RIPK1 and RIPK3 promoted TAK1 activation, suggesting a positive feedforward loop of RIPK1, RIPK3, and TAK1. Conversely, ablation of TAK1 caused caspase-dependent apoptosis, in which Ripk3 deletion did not block cell death either in vivo or in vitro. Our results reveal that TAK1 activation drives RIPK3-dependent necrosis and inhibits apoptosis. TAK1 acts as a switch between apoptosis and necrosis.

scholarly journals Designing a chimeric subunit vaccine for influenza virus, based on HA2, M2e and CTxB: a bioinformatics study

2020 ◽  
Vol 21 (1) ◽  
Author(s):  
Davod Jafari ◽  
Sara Malih ◽  
Mohammad Mahmoudi Gomari ◽  
Marzieh Safari ◽  
Rasool Jafari ◽  
...  
Keyword(s):  
Influenza Virus ◽  
Half Life ◽  
3D Structure ◽  
Three Dimensional ◽  
Influenza Viruses ◽  
Dimensional Structure ◽  
Post Translational Modification ◽  
H7n9 Subtype ◽  
Life Threatening ◽  
Chimeric Vaccine

Abstract Background Type A influenza viruses are contagious and even life-threatening if left untreated. So far, no broadly protective vaccine is available due to rapid antigenic changes and emergence of new subtypes of influenza virus. In this study, we exploited bioinformatics tools in order to design a subunit chimeric vaccine from the antigenic and highly conserved regions of HA and M2 proteins of H7N9 subtype of influenza virus. We used mucosal adjuvant candidates, including CTxB, STxB, ASP-1, and LTB to stimulate mucosal immunity and analyzed the combination of HA2, M2e, and the adjuvant. Furthermore, to improve the antigen function and to maintain their three-dimensional structure, 12 different linkers including six rigid linkers and six flexible linkers were used. The 3D structure model was generated using a combination of homology and ab initio modeling methods and the molecular dynamics of the model were analyzed, either. Results Analysis of different adjuvants showed that using CtxB as an adjuvant, results in higher overall vaccine stability and higher half-life among four adjuvant candidates. Fusion of antigens and the CTxB in the form of M2e-linker-CTxB-linker-HA2 has the most stability and half life compared to other combination forms. Furthermore, the KPKPKP rigid linker showed the best result for this candidate vaccine among 12 analyzed linkers. The changes in the vaccine 3D structure made by linker insertion found to be negligible, however, although small, the linker insertion between the antigens causes the structure to change slightly. Eventually, using predictive tools such as Ellipro, NetMHCpan I and II, CD4episcore, CTLpred, BepiPred and other epitope analyzing tools, we analyzed the conformational and linear epitopes of the vaccine. The solubility, proteasome cleavage sites, peptidase and potential chemical cutters, codon optimization, post translational modification were also carried out on the final vaccine. Conclusions It is concluded that M2e-Linker-CTxB-Linker-HA2 combination of chimeric vaccine retains its 3D structure and antigenicity when KPKPKP used as linker and CTxB used as adjuvant.

The Cytoskeleton and Cell Signaling: Component Localization and Mechanical Coupling

1998 ◽  
Vol 78 (3) ◽  
pp. 763-781 ◽  
Author(s):  
PAUL A. JANMEY
Keyword(s):  
Cell Signaling ◽  
Intracellular Signaling ◽  
Network Formation ◽  
Three Dimensional ◽  
Transmembrane Receptors ◽  
Mechanical Coupling ◽  
Rapid Responses ◽  
Intracellular Ca ◽  
Lipid Kinases ◽  
Extracellular Environment

Janmey, Paul A. The Cytoskeleton and Cell Signaling: Component Localization and Mechanical Coupling. Physiol. Rev. 78: 763–781, 1998. — The three-dimensional intracellular network formed by the filamentous polymers comprising the cytoskeletal affects the way cells sense their extracellular environment and respond to stimuli. Because the cytoskeleton is viscoelastic, it provides a continuous mechanical coupling throughout the cell that changes as the cytoskeleton remodels. Such mechanical effects, based on network formation, can influence ion channel activity at the plasma membrane of cells and may conduct mechanical stresses from the cell membrane to internal organelles. As a result, both rapid responses such as changes in intracellular Ca2+ and slower responses such as gene transcription or the onset of apoptosis can be elicited or modulated by mechanical perturbations. In addition to mechanical features, the cytoskeleton also provides a large negatively charged surface on which many signaling molecules including protein and lipid kinases, phospholipases, and GTPases localize in response to activation of specific transmembrane receptors. The resulting spatial localization and concomitant change in enzymatic activity can alter the magnitude and limit the range of intracellular signaling events.

Cellular Consequences of the Initiation of Blood Coagulation

1999 ◽  
Vol 82 (08) ◽  
pp. 183-192 ◽  
Author(s):  
Eric Camerer ◽  
John-Arne Røttingen ◽  
Merete Thune Wiiger ◽  
Elisabet Gjernes ◽  
Hans Prydz
Keyword(s):  
Endothelial Cells ◽  
Blood Coagulation ◽  
Intracellular Signaling ◽  
Blood Clotting ◽  
Factor Viia ◽  
Three Dimensional ◽  
Factor Xa ◽  
Factor Vii ◽  
Dimensional Structure ◽  
Major Player

IntroductionThis paper reviews some of the cell biological aspects of the consequences of blood clotting initiation. These intracellular events occur in cells carrying tissue factor (TF) when its ligand, factor VIIa, is bound to the receptor-like TF surface molecules. The intracellular signaling generated by this ligand/receptor binding and some of its consequences are described and parallel experiments with factor Xa are discussed.The role of TF as a major player in the initiation of blood coagulation has been known since the last century1,2 and is now characterized in molecular detail. Research on TF, for a long period and for obvious reasons, concentrated on its essential role as a cofactor in this process. Its importance in the development of clinical thrombosis, be it venous or arterial, has been appreciated since it was discovered that monocytes and macrophages3 and endothelial cells,4 under certain conditions, could be induced to synthesize TF. This contributed to answering the previously unresolved question about how TF got into contact with the flowing blood in the absence of any trauma. We later demonstrated that the TF induction process, in many cases, is subject to down-regulation by cAMP5,6 and that Ca2+ influx can induce the synthesis,5,6 along with a large number of other compounds.7 We also showed that protein kinase C was a mediator in at least some of these inducing pathways.8 The purification of TF in 19739 showed that TF was an integral membrane protein. By 1977 it was clear that TF likely participated in functions other than blood clotting.10 The cloning of the gene for TF11-14 suggested that, structurally, TF was a member of the Class II cytokine receptor family.15 To fulfil the criteria for being a true receptor, it also needed a specific and high-affinity ligand, which it has in factor VII. Also, to be classified as a true receptor, ligand binding should generate an intracellular signal. In 1992, we presented the first report of such a signal in the form of Ca2+ peaks. These peaks were triggered by the addition of factor VIIa to endothelial cells carrying TF on their surface as a result of exposure to interleukin 1β. These signals were characterized further16,17 and were thought to render final proof for the function of the TF receptor.This review discusses our findings with respect to TF/factor VIIa-induced intracellular Ca2+-signaling and concludes that there is likely a two-component receptor. The more consequential question—whether this intracellular signaling leads to altered gene expression and to other phenotypic changes—is also raised. The establishment of knockout mice18–20 and efforts to solve the three-dimensional structure of this complex by x-ray diffraction21–24 are not reviewed extensively.

scholarly journals Epitope mapping of a monoclonal antibody to human glutathione transferase P1–1 the binding of which is inhibited by glutathione

1997 ◽  
Vol 321 (2) ◽  
pp. 531-536
Author(s):  
Takenori TAKAHATA ◽  
Shigeki TSUCHIDA ◽  
Masashi OOMURA ◽  
Takashi MATSUMOTO ◽  
Junichi AZUMI ◽  
...  
Keyword(s):  
Amino Acid ◽  
Epitope Mapping ◽  
Glutathione Transferase ◽  
Three Dimensional ◽  
Cysteine Residue ◽  
Cross Reactivity ◽  
Dimensional Structure ◽  
Amino Acid Residues ◽  
Steric Configuration ◽  
Terminal Amino

Although the three-dimensional structure of human glutathione transferase (GST) P1Ő1 crystallized with a GSH analogue has been reported, its structure in the non-complexed form has not been determined. Four monoclonal antibodies to GST P1Ő1 were produced to facilitate structural analysis. Of these, one, clone d-1 of IgG2a isotype, dose-dependently inhibited the activity of GST P1Ő1 but did not affect the activities of either GST A1Ő1 or M1Ő1. On immunoblotting, the antibody reacted strongly with GST P1Ő1 and weakly with rat GST-P and mouse GST-II, indicating cross-reactivity with Pi-class forms but preferential reactivity with GST P1Ő1. When GST P1Ő1 and the antibody were incubated in the presence of 60 ƁM GSH, no inhibition of activity was found, whereas 1-chloro-2,4-dinitrobenzene had no effect at concentrations up to 10 ƁM. The binding of GST P1Ő1 to antibody adsorbed to Protein AŐSepharose was also prevented by both 0.1 mM GSH and N-ethylmaleimide treatment. Trypsin digests of GST P1Ő1 were resolved by HPLC and a peptide that reacted with the antibody was detected by absorption experiments. N-Terminal amino acid sequencing revealed the peptide to be in the C-terminal portion of the enzyme, stretching from amino acid residues 198 to 208. A synthetic peptide of this sequence also absorbed the antibody. These results suggest that both GSH bound to the active site and N-ethylmaleimide bound to the cysteine residue repress antibody binding to the C-terminal region. Thus this antibody may be useful for examining the steric configuration of the C-terminal and other regions of GST P1Ő1 in the absence of GSH.

scholarly journals Perturbation of ubiquitin homeostasis promotes macrophage oxidative defenses

2018 ◽  
Author(s):  
Marie-Eve Charbonneau ◽  
Karla D. Passalacqua ◽  
Susan E. Hagen ◽  
Hollis D. Showalter ◽  
Christiane E. Wobus ◽  
...  
Keyword(s):  
Inflammatory Responses ◽  
Specific Pattern ◽  
Innate Immune ◽  
Signaling Cascades ◽  
Innate Immune Responses ◽  
Post Translational Modification ◽  
Downstream Signaling ◽  
Cellular Processes ◽  
Phagocyte Nadph Oxidase ◽  
Protein Ubiquitination

Innate immune responses rely on specific pattern recognition receptors that induce downstream signaling cascades and promote inflammatory responses. Emerging evidence suggests that cells may also recognize alterations in cellular processes induced by infection. Protein ubiquitination is a post-translational modification essential for maintaining cellular homeostasis, and infection can cause global alterations in the host ubiquitin proteome. Here we used a chemical biology approach to perturb the cellular ubiquitin proteome as a simplified model to study the direct effect of ubiquitin homeostasis on macrophage responses. We show that perturbation of ubiquitin homeostasis results in a rapid and transient burst of reactive oxygen species (ROS) that promotes macrophage anti-infective capacity. ROS production was dependent on the activity of the phagocyte NADPH oxidase NOX2 and was associated with an increase in intracellular calcium. Our findings suggest that major changes in the host ubiquitin landscape may be a potent signal to rapidly deploy innate immune defenses.

scholarly journals A novel conserved family of Macro-like domains—putative new players in ADP-ribosylation signaling

PeerJ ◽  
2019 ◽  
Vol 7 ◽  
pp. e6863 ◽  
Author(s):  
Małgorzata Dudkiewicz ◽  
Krzysztof Pawłowski
Keyword(s):  
Functional Data ◽  
Inflammatory Diseases ◽  
Sequence Similarity ◽  
Three Dimensional ◽  
Dimensional Structure ◽  
Post Translational Modification ◽  
Reading Frame ◽  
Adp Ribosylation ◽  
Mapping Sequence ◽  
Sequence Similarity Analysis

The presence of many completely uncharacterized proteins, even in well-studied organisms such as humans, seriously hampers a full understanding of the functioning of living cells. One such example is the human protein C12ORF4, which belongs to the DUF2362 family, present in many eukaryotic lineages and conserved in metazoans. The only functional information available on C12ORF4 (Chromosome 12 Open Reading Frame 4) is its involvement in mast cell degranulation and its being a genetic cause of autosomal intellectual disability. Bioinformatics analysis of the DUF2362 family provides strong evidence that it is a novel member of the Macro clan/superfamily. Sequence similarity analysis versus other representatives of the Macro superfamily of ADP-ribose-binding proteins and mapping sequence conservation on predicted three-dimensional structure provides hypotheses regarding the molecular function for members of the DUF2362 family. For example, the available functional data suggest a possible role for C12ORF4 in ADP-ribosylation signaling in asthma and related inflammatory diseases. This novel family appears to be a likely novel ADP-ribosylation “reader” and “eraser,” a previously unnoticed putative new player in cell signaling by this emerging post-translational modification.

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