Inactivation of the glutathione peroxidase GPx4 by the ferroptosis‐inducing molecule RSL3 requires the adaptor protein 14‐3‐3ε

Vučković, Ana-Marija; Bosello-Travain, Valentina; Bordin, Luciana; Cozza, Giorgio; Miotto, Giovanni; Rossetto, Monica; Toppo, Stefano; Venerando, Rina; Zaccarin, Mattia; Maiorino, Matilde; Ursini, Fulvio; Roveri, Antonella

doi:10.1002/1873-3468.13631

Cited by 57 publications

(41 citation statements)

References 40 publications

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“…One of the compounds (erastin) inhibited the glutamate/cystine antiporter, which leads to a deprivation of intracellular cysteine and, thus, to loss of GSH. A second one (inhibitor of GPx4 [RSL3]) proved to inhibit GPx4 in situ (195), a phenomenon that has recently been shown to require the participation of the redox-regulated adaptor protein 14-3-3e (185). The cell death caused by these compounds was also not associated with the typical pattern of apoptosis, but was accompanied by massive lipid peroxidation; was inhibited by lipophilic antioxidants, inhibitors of iron uptake and iron chelators (43,196), therefore named ferroptosis (43); and in 2015 classified as an ''iron-dependent form of regulated cell death under the control of glutathione peroxidase 4'' (65).…”

Section: Gpx4mentioning

confidence: 99%

Regulatory Phenomena in the Glutathione Peroxidase Superfamily

Brigelius‐Flohé

Flohé

2020

Antioxidants & Redox Signaling

260

163

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Significance: The selenium-containing Glutathione peroxidases (GPxs)1-4 protect against oxidative challenge, inhibit inflammation and oxidant-induced regulated cell death. Recent Advances: GPx1 and GPx4 dampen phosphorylation cascades predominantly via prevention of inactivation of phosphatases by H 2 O 2 or lipid hydroperoxides. GPx2 regulates the balance between regeneration and apoptotic cell shedding in the intestine. It inhibits inflammation-induced carcinogenesis in the gut but promotes growth of established cancers. GPx3 deficiency facilitates platelet aggregation likely via disinhibition of thromboxane biosynthesis. It is also considered a tumor suppressor. GPx4 is expressed in three different forms. The cytosolic form proved to inhibit interleukin-1-driven nuclear factor jB activation and leukotriene biosynthesis. Moreover, it is a key regulator of ferroptosis, because it reduces hydroperoxy groups of complex lipids and silences lipoxygenases. By alternate substrate use, the nuclear form contributes to chromatin compaction. Mitochondrial GPx4 forms the mitochondrial sheath of spermatozoa and, thus, guarantees male fertility. Out of the less characterized GPxs, the cysteine-containing GPx7 and GPx8 are unique in contributing to oxidative protein folding in the endoplasmic reticulum by reacting with protein isomerase as an alternate substrate. A yeast 2-Cysteine glutathione peroxidase equipped with CP and CR was reported to sense H 2 O 2 for inducing an adaptive response. Critical Issues: Most of the findings compiled are derived from tissue culture and/or animal studies only. Their impact on human physiology is sometimes questionable. Future Directions: The expression of individual GPxs and GPx-dependent regulatory phenomena are to be further investigated, in particular in respect to human health. Antioxid. Redox Signal. 33, 498-516.

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Section: Gpx4mentioning

confidence: 99%

Regulatory Phenomena in the Glutathione Peroxidase Superfamily

Brigelius‐Flohé

Flohé

2020

Antioxidants & Redox Signaling

260

163

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“…The second well-studied ferroptosis inducer is RSL3 (RAS-selective lethal 3) that inhibits directly the activity of GPX4. It acts by alkylating the nucleophilic active-site of selenocysteine of GPX4, which interacts with the reduced form of the adaptor protein 14-3-3ε, causing the loss of lipid repair and the accumulation of lethal lipid peroxides and cell death by ferroptosis without affecting GSH and system X C − [10].…”

Section: Introductionmentioning

confidence: 99%

NCOA4-mediated ferritinophagy promotes ferroptosis induced by erastin, but not by RSL3 in HeLa cells

Gryzik

Asperti

Denardo

et al. 2021

Biochimica et Biophysica Acta (BBA) - Molecular Cell Research

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Ferroptosis is a regulated cell death characterized by a lethal accumulation of lipid peroxides due to an increase of intracellular iron and a decrease of antioxidant capacity. The reduction of antioxidant activity is obtained by using chemical agents, such as erastin and RSL3, the first one inhibiting the transmembrane cystine-glutamate antiporter causing a cysteine and glutathione depletion and the second one inactivating directly the glutathione peroxidase 4 (GPX4) respectively. The role of iron and its related proteins in supporting the formation of lipid peroxides, is not completely understood hence to try to shed light on it we generated HeLa clones with altered ferritinophagy, the ferritin degradation process, by knocking-out or overexpressing Nuclear Receptor Coactivator 4 (NCOA4), the ferritin autophagic cargo-receptor. NCOA4 deficiency abolished ferritinophagy increasing ferritin level and making the cells more resistant to erastin, but unexpectedly more sensitive to RSL3. Interestingly, we found that erastin promoted ferritinophagy in HeLa cells expressing NCOA4, increasing the free iron, lipid peroxidation and the sensitivity to ferroptosis. In contrast, RSL3 did not modulate ferritinophagy, while NCOA4 overexpression delayed RSL3-induced cell death suggesting that RSL3 mechanism of action is independent of ferritin degradation process. Therefore, the ferritin-iron release in the execution of ferroptosis seems to depend on the inducing compound, its target and downstream pathway of cell death activation.

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“…Ferroptosis occurs when the AA-OH-PE levels are sufficiently high to surpass the cellular threshold (Kagan et al, 2017). Under physiological conditions, toxic lipid peroxides are reduced to non-toxic lipid alcohols by GPX4 to protect cells against oxidative stress (Kagan et al, 2017;Zhang Z. et al, 2018;Vuckovic et al, 2020). However, substantial accumulation of lipid peroxides cannot be effectively eliminated by GPX4, and the excess lipid peroxide damages membrane integrity, leading to cell rupture and ferroptosis, which has been proven in proteomics studies (Forcina and Dixon, 2019;Fujii et al, 2019).…”

Section: Lipid Peroxidationmentioning

confidence: 97%