scholarly journals Ferroptosis Regulation by the NGLY1/NFE2L1 Pathway

2021 ◽  
Author(s):  
Giovanni C. Forcina ◽  
Lauren Pope ◽  
Magdalena Murray ◽  
Wentao Dong ◽  
Monther Abu-Remaileh ◽  
...  
Keyword(s):  
Transcription Factors ◽  
Stress Responses ◽  
Apoptotic Cell ◽  
Related Factor ◽  
Nuclear Factor ◽  
Wild Type ◽  
Functional Maturation ◽  
And Function ◽  
Oxidative Stress Responses ◽  
Broad Role

Ferroptosis is an oxidative form of non-apoptotic cell death whose transcriptional regulation is poorly understood. Cap'n'collar (CNC) transcription factors including Nuclear Factor Erythroid-2 Related Factor 1 (NFE2L1/NRF1) and NFE2L2 (NRF2) are important regulators of oxidative stress responses. Here, we report that NFE2L1 expression inhibits ferroptosis, independent of NFE2L2. NFE2L1 inhibits ferroptosis by promoting expression of the key anti-ferroptotic lipid hydroperoxidase glutathione peroxidase 4 (GPX4). NFE2L1 abundance and function are regulated post-translationally by N-glycosylation. Functional maturation of NFE2L1 requires deglycosylation by cytosolic peptide:N-glycanase 1 (NGLY1). We find that loss of NGLY1 or NFE2L1 enhances ferroptosis sensitivity. Expression of wild-type NGLY1 but not a disease-associated NGLY1 mutant inhibits ferroptosis, and this effect is dependent on the presence of NFE2L1. Enhanced ferroptosis sensitivity in NFE2L1 and NFE2L2 knockout cells can be potently reverted by expression of an NFE2L1 mutant containing eight asparagine-to-aspartate protein sequence substitutions, which mimic NGLY1-catalyzed sequence editing. Enhanced ferroptosis sensitivity in NGLY1/NFE2L1 pathway mutants could also be reversed by overexpression of NFE2L2. These results suggest that ferroptosis sensitivity is regulated by NGLY1-catalyzed NFE2L1 deglycosylation, and highlight a broad role for CNC transcription factors in ferroptosis regulation.

Clade III cytokinin response factors share common roles in response to oxidative stress responses linked to cytokinin synthesis

2021 ◽  
Vol 72 (8) ◽  
pp. 3294-3306
Author(s):  
Ariel M Hughes ◽  
H Tucker Hallmark ◽  
Lenka Plačková ◽  
Ondrej Novák ◽  
Aaron M Rashotte
Keyword(s):  
Oxidative Stress ◽  
Transcription Factors ◽  
Stress Response ◽  
Stress Responses ◽  
Oxidative Stress Response ◽  
Response Factors ◽  
Ontology Term ◽  
Regulated Expression ◽  
Cytokinin Response ◽  
Oxidative Stress Responses

Abstract Cytokinin response factors (CRFs) are transcription factors that are involved in cytokinin (CK) response, as well as being linked to abiotic stress tolerance. In particular, oxidative stress responses are activated by Clade III CRF members, such as AtCRF6. Here we explored the relationships between Clade III CRFs and oxidative stress. Transcriptomic responses to oxidative stress were determined in two Clade III transcription factors, Arabidopsis AtCRF5 and tomato SlCRF5. AtCRF5 was required for regulated expression of >240 genes that are involved in oxidative stress response. Similarly, SlCRF5 was involved in the regulated expression of nearly 420 oxidative stress response genes. Similarities in gene regulation by these Clade III members in response to oxidative stress were observed between Arabidopsis and tomato, as indicated by Gene Ontology term enrichment. CK levels were also changed in response to oxidative stress in both species. These changes were regulated by Clade III CRFs. Taken together, these findings suggest that Clade III CRFs play a role in oxidative stress response as well as having roles in CK signaling.

scholarly journals A Glutathione Peroxidase Gene from Litopenaeus vannamei Is Involved in Oxidative Stress Responses and Pathogen Infection Resistance

2022 ◽  
Vol 23 (1) ◽  
pp. 567
Author(s):  
Jin-Quan Fan ◽  
Bin-Bin Li ◽  
Qian-Ming Hong ◽  
Ze-Yu Yan ◽  
Xin-Jun Yang ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Glutathione Peroxidase ◽  
Stress Responses ◽  
Litopenaeus Vannamei ◽  
White Spot Syndrome Virus ◽  
Regulation Mechanism ◽  
Related Factor ◽  
Infection Resistance ◽  
Immune Challenges ◽  
Oxidative Stress Responses

In shrimp, several glutathione peroxidase (GPX) genes have been cloned and functionally studied. Increasing evidence suggests the genes’ involvement in white spot syndrome virus (WSSV)- or Vibrio alginolyticus-infection resistance. In the present study, a novel GXP gene (LvGPX3) was cloned in Litopenaeus vannamei. Promoter of LvGPX3 was activated by NF-E2-related factor 2. Further study showed that LvGPX3 expression was evidently accelerated by oxidative stress or WSSV or V. alginolyticus infection. Consistently, downregulated expression of LvGPX3 increased the cumulative mortality of WSSV- or V. alginolyticus-infected shrimp. Similar results occurred in shrimp suffering from oxidative stress. Moreover, LvGPX3 was important for enhancing Antimicrobial peptide (AMP) gene expression in S2 cells with lipopolysaccharide treatment. Further, knockdown of LvGPX3 expression significantly suppressed expression of AMPs, such as Penaeidins 2a, Penaeidins 3a and anti-lipopolysaccharide factor 1 in shrimp. AMPs have been proven to be engaged in shrimp WSSV- or V. alginolyticus-infection resistance; it was inferred that LvGPX3 might enhance shrimp immune response under immune challenges, such as increasing expression of AMPs. The regulation mechanism remains to be further studied.

scholarly journals Deficiency in the double-stranded RNA binding protein HYPONASTIC LEAVES1 increases sensitivity to the endoplasmic reticulum stress inducer tunicamycin in Arabidopsis

2019 ◽  
Vol 12 (1) ◽  
Author(s):  
Rikako Hirata ◽  
Kei-ichiro Mishiba ◽  
Nozomu Koizumi ◽  
Yuji Iwata
Keyword(s):  
Endoplasmic Reticulum ◽  
Er Stress ◽  
Stress Responses ◽  
Rna Binding ◽  
Transcriptional Response ◽  
Mirna Biogenesis ◽  
Loss Of Function ◽  
Wild Type ◽  
Protein Coding ◽  
And Function

Abstract Objective microRNA (miRNA) is a small non-coding RNA that regulates gene expression by sequence-dependent binding to protein-coding mRNA in eukaryotic cells. In plants, miRNA plays important roles in a plethora of physiological processes, including abiotic and biotic stress responses. The present study was conducted to investigate whether miRNA-mediated regulation is important for the endoplasmic reticulum (ER) stress response in Arabidopsis. Results We found that hyl1 mutant plants are more sensitive to tunicamycin, an inhibitor of N-linked glycosylation that causes ER stress than wild-type plants. Other miRNA-related mutants, se and ago1, exhibited similar sensitivity to the wild-type, indicating that the hypersensitive phenotype is attributable to the loss-of-function of HYL1, rather than deficiency in general miRNA biogenesis and function. However, the transcriptional response of select ER stress-responsive genes in hyl1 mutant plants was indistinguishable from that of wild-type plants, suggesting that the loss-of-function of HYL1 does not affect the ER stress signaling pathways.

scholarly journals Hypoxia preconditioning promotes endurance exercise capacity of mice by activating skeletal muscle Nrf2

2019 ◽  
Vol 127 (5) ◽  
pp. 1267-1277
Author(s):  
Linjia Wang ◽  
Simin Yang ◽  
Lu Yan ◽  
Hao Wei ◽  
Jianxiong Wang ◽  
...  
Keyword(s):  
Skeletal Muscle ◽  
Exercise Capacity ◽  
Treadmill Exercise ◽  
Related Factor ◽  
Nuclear Factor ◽  
Wild Type ◽  
Hypoxia Preconditioning ◽  
Nrf2 Knockout ◽  
Exercise Induced ◽  
Induced Changes

Elite endurance athletes are used to train under hypoxic/high-altitude conditions, which can elicit certain stress responses in skeletal muscle and helps to improve their physical performance. Nuclear factor erythroid 2-related factor 2 (Nrf2) regulates cellular redox homeostasis and metabolism in skeletal muscle, playing important roles in adaptation to various stresses. In this study, Nrf2 knockout (KO) and wild-type (WT) mice were preconditioned to 48 h of hypoxia exposure (11.2% oxygen), and the effects of hypoxia preconditioning (HP) on exercise capacity and exercise-induced changes of antioxidant status, energetic metabolism, and mitochondrial adaptation in skeletal muscle were evaluated. Nrf2 knockout (KO) and wild-type (WT) mice were exposed to normoxia or hypoxia for 48 h before taking incremental treadmill exercise to exhaustion under hypoxia. The skeletal muscles were collected immediately after the incremental treadmill exercise to evaluate the impacts of HP and Nrf2 on the exercise-induced changes. The results indicate the absence of Nrf2 did not affect exercise capacity, although the mRNA expression of certain muscular genes involved in antioxidant, glycogen and fatty acid catabolism was decreased in Nrf2 KO mice. However, 48-h HP enhanced exercise capacity in WT mice but not in Nrf2 KO mice, and the exercise capacity of WT mice was significantly higher than that of Nrf2 KO mice. These findings suggest HP promotes exercise capacity of mice with the participation of the Nrf2 signal in skeletal muscle. NEW & NOTEWORTHY Hypoxia preconditioning (HP) activated the nuclear factor erythroid 2-related factor 2 (Nrf2) signal, which was involved in HP-elicited adaptation responses to hypoxia, oxidative, and metabolic stresses in skeletal muscle. On the other hand, Nrf2 deficiency abolished the enhanced exercise capacity after the 48-h HP. Our results indicate that Nrf2 plays an essential role in the exercise capacity-enhancing effect of HP, possibly by modulating muscular antioxidative responses, the mRNA expression of muscular genes involved in glycogen and fatty acid metabolism, as well as mitochondrial biogenesis, and through the cross talk with AMPK and hypoxia-inducible factor-1α signaling.

scholarly journals The Transcriptional Response to a Peroxisome Proliferator-activated Receptor α Agonist Includes Increased Expression of Proteome Maintenance Genes

2004 ◽  
Vol 279 (50) ◽  
pp. 52390-52398 ◽  
Author(s):  
Steven P. Anderson ◽  
Paul Howroyd ◽  
Jie Liu ◽  
Xun Qian ◽  
Rainer Bahnemann ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Stress Responses ◽  
Transcriptional Response ◽  
Lipid Homeostasis ◽  
Peroxisome Proliferator ◽  
Wild Type ◽  
Peroxisome Proliferator Activated Receptor ◽  
Proteasomal Genes ◽  
Oxidative Stress Responses

The nuclear receptor peroxisome proliferator-activated receptor α (PPARα), in addition to regulating lipid homeostasis, controls the level of tissue damage after chemical or physical stress. To determine the role of PPARα in oxidative stress responses, we examined damage after exposure to chemicals that increase oxidative stress in wild-type or PPARα-null mice. Primary hepatocytes from wild-type but not PPARα-null mice pretreated with the PPAR pan-agonist WY-14,643 (WY) were protected from damage to cadmium and paraquat. The livers from intact wild-type but not PPARα-null mice were more resistant to damage after carbon tetrachloride treatment. To determine the molecular basis of the protection by PPARα, we identified by transcript profiling genes whose expression was altered by a 7-day exposure to WY in wild-type and PPARα-null mice. Of the 815 genes regulated by WY in wild-type mice (p≤ 0.001; ≥1.5-fold or ≤-1.5-fold), only two genes were regulated similarly by WY in PPARα-null mice. WY increased expression of stress modifier genes that maintain the health of the proteome, including those that prevent protein aggregation (heat stress-inducible chaperones) and eliminate damaged proteins (proteasome components). Although the induction of proteasomal genes significantly overlapped with those regulated by 1,2-dithiole-3-thione, an activator of oxidant-inducible Nrf2, WY increased expression of proteasomal genes independently of Nrf2. Thus, PPARα controls the vast majority of gene expression changes after exposure to WY in the mouse liver and protects the liver from oxidant-induced damage, possibly through regulation of a distinct set of proteome maintenance genes.

scholarly journals Negative regulation of nuclear factor-kappaB activation and function by glucocorticoids

2002 ◽  
Vol 28 (2) ◽  
pp. 69-78 ◽  
Author(s):  
WY Almawi ◽  
OK Melemedjian
Keyword(s):  
Transcription Factors ◽  
Transcriptional Activation ◽  
Promoter Region ◽  
Nuclear Translocation ◽  
Nuclear Factor Kappab ◽  
Nuclear Factor ◽  
Creb Binding Protein ◽  
Transcriptional Initiation ◽  
Nf Kappab ◽  
And Function

Glucocorticoids (GCs) exert their anti-inflammatory and antiproliferative effects principally by inhibiting the expression of cytokines and adhesion molecules. Mechanistically, GCs diffuse through the cell membrane, and bind to their inactive cytosolic receptors (GRs), which then undergo conformational modifications that allow for their nuclear translocation. In the nucleus, activated GRs modulate transcriptional events by directly associating with DNA elements, compatible with the GCs response elements (GRE) motif, and located in variable copy numbers and at variable distances from the TATA box, in the promoter region of GC-responsive genes. In addition, activated GRs also acted by antagonizing the activity of transcription factors, in particular nuclear factor-kappaB (NF-kappaB), by direct and indirect mechanisms. GCs induced gene transcription and protein synthesis of the NF-kappaB inhibitor, IkappaB. Activated GR also antagonized NF-kappaB activity through protein-protein interaction involving direct complexing with, and inhibition of, NF-kappaB binding to DNA (Simple Model), or association with NF-kappaB bound to the kappaB DNA site (Composite Model). In addition, and according to the Transmodulation Model, GRE-bound GR may interact with and inhibit the activity of kappaB-bound NF-kappaB via a mechanism involving cross-talk between the two transcription factors. Lastly, GR may compete with NF-kappaB for nuclear coactivators, including CREB binding protein and p300, thereby reducing and inhibiting transcriptional activation by NF-kappaB. It should be noted that, in exerting its effect, activated GR did not affect the correct assembly of the pre-initiation (DAB) complex, but acted rather more proximally in inhibiting the correct assembly of transcription factors in the promoter region, and thus transcriptional initiation.

scholarly journals Complexity of CNC Transcription Factors As Revealed by Gene Targeting of the Nrf3 Locus

2004 ◽  
Vol 24 (8) ◽  
pp. 3286-3294 ◽  
Author(s):  
Anna Derjuga ◽  
Tania S. Gourley ◽  
Teresa M. Holm ◽  
Henry H. Q. Heng ◽  
Ramesh A. Shivdasani ◽  
...  
Keyword(s):  
Transcription Factors ◽  
Leucine Zipper ◽  
B Lymphocyte ◽  
Gross Anatomy ◽  
Related Factor ◽  
Wild Type ◽  
Basic Leucine Zipper ◽  
Mild Phenotype ◽  
Age Progression

ABSTRACT Cap'n'collar (CNC) family basic leucine zipper transcription factors play crucial roles in the regulation of mammalian gene expression and development. To determine the in vivo function of the CNC protein Nrf3 (NF-E2-related factor 3), we generated mice deficient in this transcription factor. We performed targeted disruption of two Nrf3 exons coding for CNC homology, basic DNA-binding, and leucine zipper dimerization domains. Nrf3 null mice developed normally and revealed no obvious phenotypic differences compared to wild-type animals. Nrf3 −/− mice were fertile, and gross anatomy as well as behavior appeared normal. The mice showed normal age progression and did not show any apparent additional phenotype during their life span. We observed no differences in various blood parameters and chemistry values. We infected wild-type and Nrf3 −/− mice with acute lymphocytic choriomeningitis virus and found no differences in these animals with respect to their number of virus-specific CD8 and CD4 T cells as well as their B-lymphocyte response. To determine whether the mild phenotype of Nrf3 null animals is due to functional redundancy, we generated mice deficient in multiple CNC factors. Contrary to our expectations, an absence of Nrf3 does not seem to cause additional lethality in compound Nrf3 −/−/Nrf2 −/− and Nrf3 −/−/p45 −/− mice. We hypothesize that the role of Nrf3 in vivo may become apparent only after appropriate challenge to the mice.

scholarly journals Bax and Bak can localize to the endoplasmic reticulum to initiate apoptosis

2003 ◽  
Vol 162 (1) ◽  
pp. 59-69 ◽  
Author(s):  
Wei-Xing Zong ◽  
Chi Li ◽  
Georgia Hatzivassiliou ◽  
Tullia Lindsten ◽  
Qian-Chun Yu ◽  
...  
Keyword(s):  
Conformational Changes ◽  
Stress Responses ◽  
Parp Cleavage ◽  
Mitochondrial Outer Membrane ◽  
Wild Type ◽  
Caspase Activation ◽  
Caspase 12 ◽  
Parallel Pathway ◽  
Caspase 7 ◽  
And Function

Bax and Bak play a redundant but essential role in apoptosis initiated by the mitochondrial release of apoptogenic factors. In addition to their presence at the mitochondrial outer membrane, Bax and Bak can also localize to the ER. Agents that initiate ER stress responses can induce conformational changes and oligomerization of Bax on the ER as well as on mitochondria. In wild-type cells, this is associated with caspase 12 cleavage that is abolished in bax−/−bak−/− cells. In bax−/−bak−/− cells, introduction of Bak mutants selectively targeted to either mitochondria or the ER can induce apoptosis. However, ER-targeted, but not mitochondria-targeted, Bak leads to progressive depletion of ER Ca2+ and induces caspase 12 cleavage. In contrast, mitochondria-targeted Bak leads to enhanced caspase 7 and PARP cleavage in comparison with the ER-targeted Bak. These findings demonstrate that in addition to their functions at mitochondria, Bax and Bak also localize to the ER and function to initiate a parallel pathway of caspase activation and apoptosis.

scholarly journals Anti-Oxidative, Anti-Inflammatory and Anti-Apoptotic Effects of Flavonols: Targeting Nrf2, NF-ҡB and p53 Pathways in Neurodegeneration

Antioxidants ◽  
2021 ◽  
Vol 10 (10) ◽  
pp. 1628
Author(s):  
Maja Jazvinšćak Jembrek ◽  
Nada Oršolić ◽  
Lucija Mandić ◽  
Anja Sadžak ◽  
Suzana Šegota
Keyword(s):  
Transcription Factors ◽  
Cellular Response ◽  
Molecular Mechanisms ◽  
Therapeutic Potential ◽  
Nuclear Factor Κb ◽  
Related Factor ◽  
Nuclear Factor ◽  
Anti Inflammatory ◽  
New Treatments ◽  
Apoptotic Effects

Neurodegenerative diseases are one of the leading causes of disability and death worldwide. Intracellular transduction pathways that end in the activation of specific transcription factors are highly implicated in the onset and progression of pathological changes related to neurodegeneration, of which those related to oxidative stress (OS) and neuroinflammation are particularly important. Here, we provide a brief overview of the key concepts related to OS- and neuroinflammation-mediated neuropathological changes in neurodegeneration, together with the role of transcription factors nuclear factor erythroid 2-related factor 2 (Nrf2) and nuclear factor-κB (NF-κB). This review is focused on the transcription factor p53 that coordinates the cellular response to diverse genotoxic stimuli, determining neuronal death or survival. As current pharmacological options in the treatment of neurodegenerative disease are only symptomatic, many research efforts are aimed at uncovering efficient disease-modifying agents. Natural polyphenolic compounds demonstrate powerful anti-oxidative, anti-inflammatory and anti-apoptotic effects, partially acting as modulators of signaling pathways. Herein, we review the current understanding of the therapeutic potential and limitations of flavonols in neuroprotection, with emphasis on their anti-oxidative, anti-inflammatory and anti-apoptotic effects along the Nrf2, NF-κB and p53 pathways. A better understanding of cellular and molecular mechanisms of their action may pave the way toward new treatments.

Understanding life and death decisions in human leukaemias

2014 ◽  
Vol 42 (4) ◽  
pp. 747-751
Author(s):  
David J. MacEwan ◽  
Lawrence N. Barrera ◽  
Sujitra Keadsanti ◽  
Stuart A. Rushworth ◽  
Niraj M. Shah ◽  
...  
Keyword(s):  
Transcription Factor ◽  
Apoptotic Cell ◽  
Chemotherapy Resistance ◽  
Nuclear Factor Κb ◽  
Related Factor ◽  
Nuclear Factor ◽  
Cellular Processes ◽  
Cell Death Mechanisms ◽  
Factor Α ◽  
Human Leukaemia

Human leukaemia cells have an often unique ability to either undergo apoptotic cell death mechanisms or, at other times, undergo proliferative expansion, sometimes to the same stimulus such as the pluripotent cytokine TNFα (tumour necrosis factor α). This potential for life/death switching helps us to understand the molecular signalling machinery that underlies these cellular processes. Furthermore, looking at the involvement of these switching signalling pathways that may be aberrant in leukaemia informs us of their importance in cancer tumorigenesis and how they may be targeted pharmacologically to treat various types of human leukaemias. Furthermore, these important pathways may play a crucial role in acquired chemotherapy resistance and should be studied further to overcome in the clinic many drug-resistant forms of blood cancers. In the present article, we uncover the relationship that exists in human leukaemia life/death switching between the anti-apoptotic pro-inflammatory transcription factor NF-κB (nuclear factor κB) and the cytoprotective antioxidant-responsive transcription factor Nrf2 (nuclear factor-erythroid 2-related factor 2). We also discuss recent findings that reveal a major role for Btk (Bruton's tyrosine kinase) in both lymphocytic and myeloid forms of human leukaemias and lymphomas.

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