scholarly journals Keap1 recognizes EIAV early accessory protein Rev to promote antiviral defense

2021 ◽  
Author(s):  
Yan Wang ◽  
GuanQin Ma ◽  
Xue-Feng Wang ◽  
Lei Na ◽  
Xing Guo ◽  
...  
Keyword(s):  
Antioxidant Enzymes ◽  
Immune Regulation ◽  
Molecular Mechanisms ◽  
Direct Interaction ◽  
Accessory Protein ◽  
Antiviral Defense ◽  
Defensive Response ◽  
Rna Transport ◽  
Cellular Resistance ◽  
Viral Susceptibility

The Nrf2/Keap1 axis plays a complex role in viral susceptibility, virus-associated inflammation and immune regulation. However, whether or how the Nrf2/Keap1 axis is involved in the interactions between equine lentiviruses and their hosts remains unclear. Here, we demonstrate that the Nrf2/Keap1 axis was activated during EIAV infection. Mechanistically, EIAV-Rev competitively binds to Keap1 and releases Nrf2 from Keap1-mediated repression, leading to the accumulation of Nrf2 in the nucleus and promoting Nrf2 responsive genes transcription. Subsequently, we demonstrated that the Nrf2/Keap1 axis represses EIAV replication via two independent molecular mechanisms: directly increasing antioxidant enzymes to promote effective cellular resistance against EIAV infection, and repression of Rev-mediated RNA transport through direct interaction between Keap1 and Rev. Together, these data suggest that activation of the Nrf2/Keap1 axis mediates a passive defensive response to combat EIAV infection. The Nrf2/Keap1 axis could be a potential target for developing the strategies for combating EIAV infection.

Abstract MP58: Tissue And Sex Specific Effects Of Gstm1 Deletion In Mouse Models

Hypertension ◽  
2021 ◽  
Vol 78 (Suppl_1) ◽  
Author(s):  
Yves Wang ◽  
Nhu Nguyen ◽  
Keith Nehrke ◽  
Paul S Brookes ◽  
Thu H Le
Keyword(s):  
Oxidative Stress ◽  
Antioxidant Enzymes ◽  
Mouse Model ◽  
Molecular Mechanisms ◽  
Ischemia Reperfusion Injury ◽  
Ischemia Reperfusion ◽  
Antioxidant Properties ◽  
Iri Model ◽  
Increased Risk ◽  
Study Gene Expression

The glutathione S-transferase ( Gst ) gene family encodes antioxidant enzymes. In humans, a common null allele deletion variant of GST μ-1 ( GSTM1 ) is highly prevalent across populations and is associated with increased risk and progression of various diseases. Using a Gstm1 knockout (KO) mouse model, we previously showed that KO mice with angiotensin II-induced hypertension (HTN) have increased kidney injury compared to wild-type (WT) controls, mediated by elevated oxidative stress. In the same mouse model, we have recently reported that in a Langendorff-perfused cardiac ischemia-reperfusion injury (IRI) model, where damage is also mediated by oxidative stress, male KO hearts are protected while females are not. Here, we investigated the molecular mechanisms for this difference in male hearts. WT and KO mice of both sexes were studied at 12-20 weeks of age. Hearts were snap frozen at baseline and after 25 min of global ischemia, and kidneys were collected at baseline and 4 weeks following HTN induction. A panel of 18 Gst genes were probed by qPCR from baseline hearts and kidneys of both sexes. Global metabolites were assayed using Metabolon, Inc. from hearts of both sexes and kidneys of males, at both baseline and diseased states. Analysis by qPCR (n = 3/group) showed that male, but not female, KO hearts had upregulation of other Gst s. In contrast, no significant differences between were found in male kidneys. Metabolomics (n = 6/group) detected 695 metabolites in hearts and 926 in kidneys. There were increases in several metabolites in KO vs. WT hearts including those with antioxidant properties. Notably, increases in carnosine and anserine were observed in KO male hearts but not in female hearts, while that of other antioxidant-related metabolites were observed in hearts of both sexes, but not in kidneys. HTN induced significant increases in metabolites in KO vs. WT kidneys in the pathways related to and linking methionine, cysteine, and glutathione, which were not observed in hearts. In this study, gene expression and metabolites suggest that the mechanisms compensating for the loss of GSTM1 are both tissue and sex specific. The resulting differences in antioxidant enzymes and metabolites may explain the unexpected protection for male Gstm1 KO hearts in IRI.

scholarly journals Transcriptomic Analysis of Staphylococcus xylosus in Solid Dairy Matrix Reveals an Aerobic Lifestyle Adapted to Rind

2020 ◽  
Vol 8 (11) ◽  
pp. 1807
Author(s):  
Sabine Leroy ◽  
Sergine Even ◽  
Pierre Micheau ◽  
Anne de La Foye ◽  
Valérie Laroute ◽  
...  
Keyword(s):  
Gene Expression ◽  
Amino Acids ◽  
Antioxidant Enzymes ◽  
Dairy Products ◽  
Molecular Mechanisms ◽  
Iron Acquisition ◽  
Carbon Sources ◽  
Original System ◽  
Staphylococcus Xylosus ◽  
Genes Encoding

Staphylococcus xylosus is found in the microbiota of traditional cheeses, particularly in the rind of soft smeared cheeses. Despite its frequency, the molecular mechanisms allowing the growth and adaptation of S. xylosus in dairy products are still poorly understood. A transcriptomic approach was used to determine how the gene expression profile is modified during the fermentation step in a solid dairy matrix. S. xylosus developed an aerobic metabolism perfectly suited to the cheese rind. It overexpressed genes involved in the aerobic catabolism of two carbon sources in the dairy matrix, lactose and citrate. Interestingly, S. xylosus must cope with nutritional shortage such as amino acids, peptides, and nucleotides, consequently, an extensive up-regulation of genes involved in their biosynthesis was observed. As expected, the gene sigB was overexpressed in relation with general stress and entry into the stationary phase and several genes under its regulation, such as those involved in transport of anions, cations and in pigmentation were up-regulated. Up-regulation of genes encoding antioxidant enzymes and glycine betaine transport and synthesis systems showed that S. xylosus has to cope with oxidative and osmotic stresses. S. xylosus expressed an original system potentially involved in iron acquisition from lactoferrin.

scholarly journals Correction: Caveolin-1 inhibits expression of antioxidant enzymes through direct interaction with nuclear erythroid 2 p45-related factor-2 (Nrf2).

2020 ◽  
Vol 295 (28) ◽  
pp. 9766-9766
Author(s):  
Wen Li ◽  
Hui Liu ◽  
Jie-Sen Zhou ◽  
Jiao-Fei Cao ◽  
Xiao-Bo Zhou ◽  
...  
Keyword(s):  
Antioxidant Enzymes ◽  
Direct Interaction ◽  
Related Factor ◽  
Caveolin 1

scholarly journals The association of Plk1 with the astrin–kinastrin complex promotes formation and maintenance of a metaphase plate

2020 ◽  
Vol 134 (1) ◽  
pp. jcs251025
Author(s):  
Zoë Geraghty ◽  
Christina Barnard ◽  
Pelin Uluocak ◽  
Ulrike Gruneberg
Keyword(s):  
Molecular Mechanisms ◽  
Metaphase Plate ◽  
Direct Interaction ◽  
Mitotic Chromosomes ◽  
Spindle Formation ◽  
Bipolar Spindle ◽  
Mitotic Kinase ◽  
Spindle Poles ◽  
Chromosome Congression ◽  
Chromosome Alignment

ABSTRACTErrors in mitotic chromosome segregation can lead to DNA damage and aneuploidy, both hallmarks of cancer. To achieve synchronous error-free segregation, mitotic chromosomes must align at the metaphase plate with stable amphitelic attachments to microtubules emanating from opposing spindle poles. The astrin–kinastrin (astrin is also known as SPAG5 and kinastrin as SKAP) complex, also containing DYNLL1 and MYCBP, is a spindle and kinetochore protein complex with important roles in bipolar spindle formation, chromosome alignment and microtubule–kinetochore attachment. However, the molecular mechanisms by which astrin–kinastrin fulfils these diverse roles are not fully understood. Here, we characterise a direct interaction between astrin and the mitotic kinase Plk1. We identify the Plk1-binding site on astrin as well as four Plk1 phosphorylation sites on astrin. Regulation of astrin by Plk1 is dispensable for bipolar spindle formation and bulk chromosome congression, but promotes stable microtubule–kinetochore attachments and metaphase plate maintenance. It is known that Plk1 activity is required for effective microtubule–kinetochore attachment formation, and we suggest that astrin phosphorylation by Plk1 contributes to this process.

scholarly journals Mechanisms and therapeutic potential of interactions between human amyloids and viruses

2020 ◽  
Author(s):  
Emiel Michiels ◽  
Frederic Rousseau ◽  
Joost Schymkowitz
Keyword(s):  
Molecular Mechanisms ◽  
Driving Forces ◽  
Therapeutic Potential ◽  
Direct Interaction ◽  
Therapeutic Interventions ◽  
Microbial Pathogens ◽  
Amyloid Formation ◽  
Sequence Specificity ◽  
Affected Tissue ◽  
Virus Interactions

AbstractThe aggregation of specific proteins and their amyloid deposition in affected tissue in disease has been studied for decades assuming a sole pathogenic role of amyloids. It is now clear that amyloids can also encode important cellular functions, one of which involves the interaction potential of amyloids with microbial pathogens, including viruses. Human expressed amyloids have been shown to act both as innate restriction molecules against viruses as well as promoting agents for viral infectivity. The underlying molecular driving forces of such amyloid–virus interactions are not completely understood. Starting from the well-described molecular mechanisms underlying amyloid formation, we here summarize three non-mutually exclusive hypotheses that have been proposed to drive amyloid–virus interactions. Viruses can indirectly drive amyloid depositions by affecting upstream molecular pathways or induce amyloid formation by a direct interaction with the viral surface or specific viral proteins. Finally, we highlight the potential of therapeutic interventions using the sequence specificity of amyloid interactions to drive viral interference.

scholarly journals Paradoxical Roles of Antioxidant Enzymes: Basic Mechanisms and Health Implications

2016 ◽  
Vol 96 (1) ◽  
pp. 307-364 ◽  
Author(s):  
Xin Gen Lei ◽  
Jian-Hong Zhu ◽  
Wen-Hsing Cheng ◽  
Yongping Bao ◽  
Ye-Shih Ho ◽  
...  
Keyword(s):  
Antioxidant Enzymes ◽  
Reactive Nitrogen Species ◽  
Molecular Mechanisms ◽  
Dual Roles ◽  
Treatment Protocols ◽  
Redox Biology ◽  
Novel Treatments ◽  
Cellular Context ◽  
Health And Disease ◽  
Metabolic Interactions

Reactive oxygen species (ROS) and reactive nitrogen species (RNS) are generated from aerobic metabolism, as a result of accidental electron leakage as well as regulated enzymatic processes. Because ROS/RNS can induce oxidative injury and act in redox signaling, enzymes metabolizing them will inherently promote either health or disease, depending on the physiological context. It is thus misleading to consider conventionally called antioxidant enzymes to be largely, if not exclusively, health protective. Because such a notion is nonetheless common, we herein attempt to rationalize why this simplistic view should be avoided. First we give an updated summary of physiological phenotypes triggered in mouse models of overexpression or knockout of major antioxidant enzymes. Subsequently, we focus on a series of striking cases that demonstrate “paradoxical” outcomes, i.e., increased fitness upon deletion of antioxidant enzymes or disease triggered by their overexpression. We elaborate mechanisms by which these phenotypes are mediated via chemical, biological, and metabolic interactions of the antioxidant enzymes with their substrates, downstream events, and cellular context. Furthermore, we propose that novel treatments of antioxidant enzyme-related human diseases may be enabled by deliberate targeting of dual roles of the pertaining enzymes. We also discuss the potential of “antioxidant” nutrients and phytochemicals, via regulating the expression or function of antioxidant enzymes, in preventing, treating, or aggravating chronic diseases. We conclude that “paradoxical” roles of antioxidant enzymes in physiology, health, and disease derive from sophisticated molecular mechanisms of redox biology and metabolic homeostasis. Simply viewing antioxidant enzymes as always being beneficial is not only conceptually misleading but also clinically hazardous if such notions underpin medical treatment protocols based on modulation of redox pathways.

scholarly journals IQGAP1 binds AMPK and is required for maximum AMPK activation

2020 ◽  
pp. jbc.RA120.016193
Author(s):  
Andrew C. Hedman ◽  
Zhigang Li ◽  
Laëtitia Gorisse ◽  
Swetha Parvathaneni ◽  
Chase J. Morgan ◽  
...  
Keyword(s):  
Protein Kinase ◽  
Intracellular Signaling ◽  
Energy Homeostasis ◽  
Molecular Mechanisms ◽  
Direct Interaction ◽  
Mitogen Activated Protein Kinase ◽  
Null Cell ◽  
Ampk Signaling ◽  
In Cells

AMP-activated protein kinase (AMPK) is a fundamental component of a protein kinase cascade that is an energy sensor. AMPK maintains energy homeostasis in the cell by promoting catabolic and inhibiting anabolic pathways. Activation of AMPK requires phosphorylation by the liver kinase B1 or by the Ca2+ /calmodulin-dependent protein kinase kinase 2 (CaMKK2). The scaffold protein IQGAP1 regulates intracellular signaling pathways, such as the mitogen-activated protein kinase and AKT signaling cascades. Recent work implicates the participation of IQGAP1 in metabolic function, but the molecular mechanisms underlying these effects are poorly understood. Here, using several approaches including binding analysis with fusion proteins, siRNA-mediated gene silencing, RT-PCR, and knockout mice, we investigated whether IQGAP1 modulates AMPK signaling. In vitro analysis reveals that IQGAP1 binds directly to the α1 subunit of AMPK. In addition, we observed a direct interaction between IQGAP1 and CaMKK2, which is mediated by the IQ domain of IQGAP1. Both CaMKK2 and AMPK associate with IQGAP1 in cells. The ability of metformin and increased intracellular free Ca2+ concentrations to activate AMPK is reduced in cells lacking IQGAP1. Importantly, Ca2+-stimulated AMPK phosphorylation was rescued by re-expression of IQGAP1 in IQGAP1-null cell lines. Comparison of the fasting response in wild-type and IQGAP1-null mice revealed that transcriptional regulation of the gluconeogenesis genes PCK1 and G6PC and the fatty acid synthesis genes FASN and ACC1 is impaired in IQGAP1-null mice. Our data disclose a previously unidentified functional interaction between IQGAP1 and AMPK and suggest that IQGAP1 modulates AMPK signaling.

scholarly journals Targeting and Stability of Na/Ca Exchanger 1 in Cardiomyocytes Requires Direct Interaction with the Membrane Adaptor Ankyrin-B

2006 ◽  
Vol 282 (7) ◽  
pp. 4875-4883 ◽  
Author(s):  
Shane R. Cunha ◽  
Naina Bhasin ◽  
Peter J. Mohler
Keyword(s):  
Molecular Mechanisms ◽  
Cardiac Tissue ◽  
Direct Interaction ◽  
Binding Activity ◽  
Membrane Domains ◽  
Excitable Cells ◽  
Expression Activity ◽  
Cellular Pathways ◽  
Ankyrin B ◽  
Calcium Extrusion

Na/Ca exchanger activity is important for calcium extrusion from the cardiomyocyte cytosol during repolarization. Animal models exhibiting altered Na/Ca exchanger expression display abnormal cardiac phenotypes. In humans, elevated Na/Ca exchanger expression/activity is linked with pathophysiological conditions including arrhythmia and heart failure. Whereas the molecular mechanisms underlying Na/Ca exchanger biophysical properties are widely studied and generally well characterized, the cellular pathways and molecular partners underlying the specialized membrane localization of Na/Ca exchanger in cardiac tissue are essentially unknown. In this report, we present the first direct evidence for a protein pathway required for Na/Ca exchanger localization and stability in primary cardiomyocytes. We define the minimal structural requirements on ankyrin-B for direct Na/Ca exchanger interactions. Moreover, using ankyrin-B mutants that lack Na/Ca exchanger binding activity, and primary cardiomyocytes with reduced ankyrin-B expression, we demonstrate that direct interaction with the membrane adaptor ankyrin-B is required for the localization and post-translational stability of Na/Ca exchanger 1 in neonatal mouse cardiomyocytes. These results raise exciting new questions regarding potentially dynamic roles for ankyrin proteins in the biogenesis and maintenance of specialized membrane domains in excitable cells.

Restoration of Peroxiredoxins and Catalase Is Closely Correlated with the Level of Philadelphia Chromosome during Imatinib Therapy in CML.

Blood ◽  
2007 ◽  
Vol 110 (11) ◽  
pp. 4539-4539
Author(s):  
Kyoung-Eun Lee ◽  
Hyun-Ae Woo ◽  
Seoug-Ha Yang ◽  
Jung-Won Huh ◽  
Moon Young Choi ◽  
...  
Keyword(s):  
Antioxidant Enzymes ◽  
Intracellular Signaling ◽  
Molecular Mechanisms ◽  
Mononuclear Cells ◽  
Philadelphia Chromosome ◽  
Bone Marrow Aspiration ◽  
New Drugs ◽  
Aberrant Expression ◽  
Abl Kinase ◽  
Normal Individuals

Abstract Background: Several investigators have recently shown that activated growth factor receptors increase the relative levels of intracellular ROS and that bcr/abl kinase induces the production of ROS in hematopoietic cells. In addition, bcr-abl kinase induces self-mutagenesis via ROS to encode IM resistance. Meanwhile, two members of the peroxiredoxin family, Prx 1 or Prx 2, efficiently lowered the intracellular level of H2O2 and blocked the induction of apoptosis by ceramide, suggesting that the Prx enzymes contribute to intracellular signaling by removing H2O2. In this study, we investigated the changse in the levels of H2O2-removing enzymes like Prxs, glutathione peroxidase 1 (Gpx1), and catalase during Imatinib (IM) therapy in CML. Methods: Mononuclear cells(MNC) were isolated by standard Ficoll-Hypaque from the bone marrow aspiration at the time of diagnosis and during treatment with IM (Gleevec, Novartis, East Hanover, NJ). Standard cytogenetics analysis and RT-PCR for Philadelphia chromosomes were performed. For immunoblot analysis of antioxidant enzymes, cell lysates were fractionated by SDS-PAGE, and the separated proteins were transferred electrophoretically to a nitrocellulose membrane (Protran, Germany) and were probed with antibodies specific for Prx I, II, VI, GPx1, or catalase (AbFrontier, South Korea). Results: Samples from the diagnosis CML patients showed significantly decreased levels of Prx I, Prx II, Prx IV, and Gpx I, but also revealed an increased level of catalase. Especially prominent was the diminished ratio of Prx II to catalase in CML patients when compared with those of normal individuals. As the level of Philadelphia chromosomes decreased to that of normal individuals as the result of IM treatment, the expression levels of Prx(s) (P=0.018) and catalase (P=0.009) were restored to the levels of normal individuals. Conclusions: Decreased Prx 2 and elevated catalase levels at the time of diagnosis are closely correlated with the elevated bcr/abl kinase level in CML. The aberrant expression of those antioxidant enzymes returned to normal with IM treatment. Now, we will attempt to develop these method(s) to assess the changes of Prx(s) and catalase on the single cell level using immunohistochemistry with monoclonal Ab(s). Understanding the molecular mechanisms of changes on antioxidant might be a potent tool in developing more effective new drugs in CML.

scholarly journals Phospholipase D Activity Regulates Integrin-mediated Cell Spreading and Migration by Inducing GTP-Rac Translocation to the Plasma Membrane

2008 ◽  
Vol 19 (7) ◽  
pp. 3111-3123 ◽  
Author(s):  
Young Chan Chae ◽  
Jung Hwan Kim ◽  
Kyung Lock Kim ◽  
Hyun Wook Kim ◽  
Hye Young Lee ◽  
...  
Keyword(s):  
Plasma Membrane ◽  
Phospholipase D ◽  
Molecular Mechanisms ◽  
Direct Interaction ◽  
Cell Spreading ◽  
Small Gtpase ◽  
General Mechanism ◽  
Downstream Target ◽  
P21 Activated Kinase ◽  
And Migration

Small GTPase Rac is a crucial regulator of actin cytoskeletal rearrangement, and it plays an important role in cell spreading, migration, mitogenesis, phagocytosis, superoxide generation, and axonal growth. It is generally accepted that Rac activity is regulated by the guanosine triphosphate (GTP)/guanosine diphosphate (GDP) cycle. But, it is suggested that in addition to Rac-GTP loading, membrane localization is required for the initiation of downstream effector signaling. However, the molecular mechanisms that control the targeting of GTP-Rac to the plasma membrane remain largely unknown. Here, we have uncovered a signaling pathway linking phospholipase D (PLD) to the localized functions of Rac1. We show that PLD product phosphatidic acid (PA) acts as a membrane anchor of Rac1. The C-terminal polybasic motif of Rac1 is responsible for direct interaction with PA, and Rac1 mutated in this region is incapable of translocating to the plasma membrane and of activating downstream target p21-activated kinase upon integrin activation. Finally, we show that PA induces dissociation of Rho-guanine nucleotide dissociation inhibitor from Rac1 and that PA-mediated Rac1 localization is important for integrin-mediated lamellipodia formation, cell spreading, and migration. These results provide a novel molecular mechanism for the GTP-Rac1 localization through the elevating PLD activity, and they suggest a general mechanism for diverse cellular functions that is required localized Rac activation.

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