Gpx4 regulates iNKT cell homeostasis and function by preventing lipid peroxidation and ferroptosis
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ABSTRACT:
PROVIDER: PRJNA1126732 | ENA |
REPOSITORIES: ENA
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Project description:Invariant natural killer T (iNKT) cells are a group of innate like T cells that plays important roles in immune homeostasis and activation. We found that iNKT cells, compared to CD4+ T cells, have significantly higher levels of lipid peroxidation in both mice and humans. Proteomic analysis also demonstrated that iNKT cells express higher levels of Glutathione peroxidase 4 (Gpx4), a major antioxidant enzyme that reduces lipid peroxidation and prevents ferroptosis. T cell specific deletion of Gpx4 reduces iNKT cell population, most prominently the IFNg producing NKT1 subset. RNAseq analysis revealed IFNg signaling, cell cycle regulation, as well as mitochondrial function are perturbed by Gpx4 deletion in iNKT cells. Consistently, we detected impaired cytokine production, elevated cell proliferation and cell death, and accumulation of lipid peroxides and mitochondrial ROS in Gpx4 KO iNKT cells. Ferroptosis inhibitor, iron chelator, vitamin E and vitamin K2 can prevent ferroptosis induced by Gpx4 deficiency in iNKT cells and ameliorate the impaired function of iNKT cells due to Gpx4 inhibition. Lastly, vitamin E rescued iNKT cell population in Gpx4 KO mice. Altogether, our findings reveal the critical role of Gpx4 in regulating iNKT cell homeostasis and function, through controlling lipid peroxidation and ferroptosis.
2024-08-20 | GSE270485 | GEO
Project description:Purpose: Identification of Gpx4-dependent genes in resting and activated Treg cells Methods: RNA was purified from resting of stimulated (aCD3-CD38 for 4 h) splenic Treg cells sorted from WT or Foxp3CreGpx4fl/fl mice Conclusions: Gpx4 prevents lipid peroxidation and ferroptosis of activated Treg cells..
2021-10-31 | GSE160338 | GEO
Project description:Ferroptosis is an iron-dependent programmed cell death associated with severe kidney diseases, linked to decreased glutathione peroxidase 4 (GPX4). However, the spatial distribution of renal GPX4-mediated ferroptosis and the molecular events causing GPX4 reduction during ischemia-reperfusion (I/R) remain largely unknown. Using spatial transcriptomics, we identify that GPX4 is situated at the interface of the inner cortex and outer medulla, a hyperactive ferroptosis site post-I/R injury. We show that OTU deubiquitinase 5 (OTUD5) is a GPX4-binding protein that confers ferroptosis resistance by stabilizing GPX4. During I/R, ferroptosis is induced by mTORC1-mediated autophagy, causing OTUD5 degradation and subsequent GPX4 decay. Functionally, OTUD5 deletion intensifies renal tubular cell ferroptosis and exacerbates acute kidney injury, while AAV-mediated OTUD5 delivery mitigates ferroptosis and promotes renal function recovery from I/R injury. In this work, our study highlights a new autophagy-dependent ferroptosis module: hypoxia/ischemia-induced OTUD5 autophagy triggers GPX4 degradation, offering a potential therapeutic avenue for I/R-related kidney diseases.
2023-11-29 | GSE244330 | GEO
Project description:Characterized by lethal iron accumulation and lipid peroxidation, ferroptosis plays critical roles in liver injury, especially caused by ischemia/reperfusion (I/R) of hepatic inflow occlusion during liver operation. However, the lack of effective and safe clinical precautionary measure is still the main problem in preventing hepatic ferroptosis. Here, we found that the excessive production of reactive oxygen species could decrease the expression of Interferon (IFN)-stimulated gene DExH-box helicase 58 (DHX58) in hepatocytes, and then promote hepatic ferroptosis, while pre-treatment using IFN-α increased DHX58 expression and prevented ferroptosis during I/R injury. Mechanistically, DHX58 with RNA-binding activity could constitutively associate the mRNA of glutathione peroxidase 4 (GPX4), a crucial ferroptosis suppressor, and then recruit the m6A reader YT521-B homology domain containing 2 (YTHDC2) to promote the translation of Gpx4 mRNA in m6A-dependent manner, thus enhancing GPX4 protein level and preventing hepatic ferroptosis. Therefore, we provide mechanistic evidence for the IFN-stimulated DHX58 in promoting the translation of m6A-modified Gpx4 mRNA, and suggest the promising clinical potential of IFN-α pre-treatment in the prevention of hepatic ferroptosis.
2024-05-24 | PXD042083 | Pride
Project description:Glutathione peroxidase 4 (GPX4) utilizes glutathione (GSH) to detoxify lipid peroxidation and
plays an essential role in inhibiting ferroptosis. As a selenoprotein, GPX4 protein synthesis is
highly inefficient and energetically costly. How cells coordinate GPX4 synthesis with nutrient
availability remains unclear. In this study, integrated proteomic and functional analyses reveal
that SLC7A11-mediated cystine uptake promotes not only GSH synthesis but also GPX4 protein synthesis. Mechanistically, cyst(e)ine activates mechanistic/mammalian target of rapamycin complex 1 (mTORC1) and promotes GPX4 protein synthesis at least partly through the mTORC1-4E-BP signaling axis. Pharmacologic inhibition of mTORC1 decreases GPX4 protein levels, sensitizes cancer cells to ferroptosis, and synergizes with ferroptosis inducers (FINs) to suppress patient-derived xenograft tumor growth in vivo. Together, our results reveal a hitherto unrecognized regulatory mechanism to coordinate GPX4 protein synthesis with cyst(e)ine availability and suggest to use the combination of mTORC1 inhibitors and FINs in cancer treatment.
2020-08-25 | MSV000086009 | MassIVE
Project description:CDK4/6 inhibition is the standard of care for estrogen receptor positive (ER+) breast cancer, although cytostasis is frequently observed, and new treatment strategies that enhance efficacy are required. We performed a genome-wide CRISPR screen to identify genetic determinants of CDK4/6 inhibitors sensitivity. Multiple genes involved in oxidative stress and ferroptosis modulated palbociclib sensitivity. Depletion or inhibition of GPX4 increased sensitivity to palbociclib in ER+ breast cancer models, and sensitised triple negative breast cancer models to palbociclib, with GPX4 null xenografts being highly sensitive to palbociclib. Palbociclib induced oxidative stress and disordered lipid metabolism with lipid peroxidation, leading to a ferroptosis-sensitive state. Lipid peroxidation relied on a peroxisome AGPAT3-dependent pathway in ER+ breast cancer models, rather than the classical ACSL4 pathway. Our data demonstrate that CDK4/6 inhibition creates vulnerability to ferroptosis that could be exploited through combination with GPX4 inhibitors, enhancing sensitivity to CDK4/6 inhibition in breast cancer.
2023-06-20 | PXD043133 | Pride
Project description:Osteoarthritis (OA) is the most common joint disease and is the leading cause of chronic disability among older people. Chondrocyte death was involved in OA pathogenesis. Ferroptosis is an iron-dependent cell death associated with peroxidation of lipids. Expression of GPX4 in the OA cartilage from OA patients were significantly lower than normal cartilage.In order to analyze the mechanism of GPX4, we conducted RNA-sequencing in mouse chondrocytes with or without GPX4 knockdown.Our results showed that Gpx4 downregulation could increase the sensitivity of chondrocytes to oxidative stress and aggravate ECM degradation in chondrocytes.
2022-02-18 | GSE190184 | GEO
Project description:Gpx4 prevents Treg-cell lipid peroxidation and ferroptosis in promoting immune homeostasis and tumor immune escape
| PRJNA672969 | ENA
Project description:Ferroptosis is a form of regulated cell death driven by lipid peroxidation of polyunsaturated fatty acids (PUFAs). Endogenous PUFAs are nonconjugated PUFAs and their peroxidation proceeds via the hydrogen-atom transfer (HAT) mechanism. We previously reported that lipids with conjugated double bonds undergo lipid peroxidation mostly via a different mechanism, peroxyl radical addition (PRA), and were much more readily oxidizable than nonconjugated ones. In this study, we aim to elucidate the effects of various unsaturated lipids in sensitizing ferroptosis. We found that while some peroxidation-reactive lipids, such as 7-dehydrocholesterol, vitamins D3 and A, and coenzyme Q10, suppress ferroptosis, both nonconjugated and conjugated PUFAs enhanced cell death induced by RSL3, a ferroptosis inducer. Importantly, we showed that conjugated linolenic acid (CLA 18:3) could act as a ferroptosis inducer by itself and conjugated linoleic acid (CLA 18:2) was more potent in sensitizing cells to RSL3-induced cell death than any nonconjugated PUFAs. We next sought to elucidate the mechanism underlying the different ferroptosis-inducing potency of conjugated and nonconjugated PUFAs. Lipidomics revealed that conjugated and nonconjugated PUFAs are incorporated into distinct cellular lipid species. Furthermore, the different peroxidation mechanisms predict the formation of higher levels of reactive electrophilic aldehydes from conjugated PUFAs than nonconjugated PUFAs, which was confirmed by aldehyde-trapping and mass spectrometry. RNA sequencing revealed that protein processing in the endoplasmic reticulum and proteasome are among the most significantly upregulated pathways in cells treated with CLA 18:3, suggesting increased ER stress and activation of unfolded protein response. Significantly, using click chemistry, we observed increased protein adduction by oxidized lipids in cells treated with an alkynylated CLA 18:2 probe. These results suggest that protein damage by lipid electrophiles is a key step in ferroptosis.
2023-04-17 | GSE224249 | GEO
Project description:Ferroptosis is an iron-dependent cell death mechanism characterized by an accumulation of toxic lipid peroxides and membrane rupture. The glutathione dependent enzyme, GPX4 (glutathione peroxidase 4), prevents ferroptosis by reducing these lipid peroxides into non-toxic lipid alcohols. Ferroptosis induction by GPX4 inhibition has emerged as a vulnerability of cancer cells, thus highlighting the need to identify ferroptosis regulators that may be exploited therapeutically. Through genome-wide screens and a series of genetic, genomic, and quantitative imaging approaches, we identify the SWI-SNF ATPases BRM and BRG1 as ferroptosis suppressors. Mechanistically, they directly bind to and catalytically increase chromatin accessibility at NRF2 target loci, thus boosting NRF2 transcriptional output. This primes cells to counter lipid peroxidation and confers resistance to GPX4 inhibition and ferroptosis. Importantly, we demonstrate that the BRM/BRG1-ferroptosis connection can be leveraged to enhance the paralog dependency of BRG1-mutant lung cancer cells on BRM, especially in lines that are less sensitive to BRM inhibition or degradation. Our data reveal ferroptosis induction as a potential avenue for broadening the efficacy of BRM degraders/inhibitors and define a specific genetic context for exploiting GPX4 dependency.
2024-09-22 | GSE266343 | GEO