Chaperone-mediated autophagy is involved in the execution of ferroptosis

Wu, Zheming; Yang, Geng; Lü, Xin; Shi, Yuying; Wu, Guowei; Zhang, Mengmeng; Shan, Bing; Pan, Heling; Yuan, Junying

doi:10.1073/pnas.1819728116

Cited by 428 publications

(334 citation statements)

References 69 publications

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“…Recently, glutathione peroxidase 4 (GPX4) was reported to be a key enzyme that negatively regulates xCT-GSH-dependent ferroptosis by suppressing lipid ROS [47][48][49]. GPX4 is stabilized by the chaperone protein HSP90 [50], whose acetylation impairs chaperone activity and leads to degradation of its client proteins [51]. Therefore, vorinostat may degrade GPX4 protein via HSP90 acetylation, resulting in SASP-induced ferroptosis with ROS accumulation, although this is a hypothesis to be tested in the future.…”

Section: Discussionmentioning

confidence: 99%

xCT Inhibition Increases Sensitivity to Vorinostat in a ROS-Dependent Manner

Miyamoto

Watanabe

Boku

et al. 2020

Cancers

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As histone deacetylase inhibitors (HDACIs) have limited efficacy against solid tumors, we investigated whether and how oxidative stress is involved in sensitivity to HDACIs to develop a novel therapeutic option of HDACIs treatment. We first tested whether a reduction of the antioxidant glutathione (GSH) by glutamine deprivation affects sensitivity to a commercially available HDACI vorinostat and reactive oxygen species (ROS) accumulation. Next we investigated the relationship between a glutamate-cystine transporter xCT and the efficacy of vorinostat using siRNA of xCT and bioinformatic analyses. Finally, we verified the combinatory effects of vorinostat and the xCT inhibitor salazosulfapyridine (SASP) on ROS accumulation, cell death induction, and colony formation. Glutamine deprivation increased vorinostat-mediated cell death with ROS accumulation. Genetic ablation of xCT improved the efficacy of vorinostat, consistent with the results of public data analyses demonstrating that xCT expressions positively correlate with insensitivity to HDACIs in many types of cancer cell lines. Vorinostat caused ROS accumulation when combined with SASP, possibly resulting in synergistic ferroptosis. Our study provides a novel mechanistic insight into the mechanism underlying sensitivity to HDACIs involving xCT, suggesting xCT to be a promising predictive marker of HDACIs and rationalizing combinatory therapy of HDACIs with xCT inhibitors to induce ferroptosis.

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Section: Discussionmentioning

confidence: 99%

xCT Inhibition Increases Sensitivity to Vorinostat in a ROS-Dependent Manner

Miyamoto

Watanabe

Boku

et al. 2020

Cancers

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“…There is some evidence that GPX4 can be post‐translationally modified by tyrosine phosphorylation, N ‐glycosylation, and possibly acylation . GPX4 protein levels can also be directly regulated by chaperone‐mediated autophagy . One possibility is that regulation by these diverse post‐translational mechanisms allows GPX4 levels and activity to be tuned in a way that prevents excess lipid peroxidation while allowing for the generation of important physiological lipid signaling molecules.…”

Section: Summary and Future Directionsmentioning

confidence: 99%

GPX4 at the Crossroads of Lipid Homeostasis and Ferroptosis

2019

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Oxygen is necessary for aerobic metabolism but can cause the harmful oxidation of lipids and other macromolecules. Oxidation of cholesterol and phospholipids containing polyunsaturated fatty acyl chains can lead to lipid peroxidation, membrane damage, and cell death. Lipid hydroperoxides are key intermediates in the process of lipid peroxidation. The lipid hydroperoxidase glutathione peroxidase 4 (GPX4) converts lipid hydroperoxides to lipid alcohols, and this process prevents the iron (Fe2+)‐dependent formation of toxic lipid reactive oxygen species (ROS). Inhibition of GPX4 function leads to lipid peroxidation and can result in the induction of ferroptosis, an iron‐dependent, non‐apoptotic form of cell death. This review describes the formation of reactive lipid species, the function of GPX4 in preventing oxidative lipid damage, and the link between GPX4 dysfunction, lipid oxidation, and the induction of ferroptosis.

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“…It is also intriguing that HO1 and HO2 are targeted by different protein degradation machinery. CMA has recently been shown to be involved in the execution of ferroptosis, a necrosis related to iron overload (48). It is possible that defects in heme biosynthesis that leads to cellular iron overload induces ferroptosis (40).…”

Section: Discussionmentioning

confidence: 99%

Absence of heme at the catalytic site of heme oxygenase-2 triggers its lysosomal degradation

Liu

Dumbrepatil

Fleischhacker

et al. 2020

Preprint

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Heme oxygenase-2 (HO2) and −1 (HO1) catalyze heme degradation to biliverdin, CO, and iron, forming an essential link in the heme metabolism network. Tight regulation of the cellular levels and catalytic activities of HO1 and HO2 is important for maintaining heme homeostasis. While transcriptional control of HO1 expression has been well-studied, how the cellular levels and activity of HO2 are regulated remains unclear. Here, the mechanism of post-translational regulation of cellular HO2 level by heme is elucidated. Under heme deficient conditions, HO2 is destabilized and targeted for degradation. In HO2, three heme binding sites are potential targets of heme-dependent regulation: one at its catalytic site; the others at its two heme regulatory motifs (HRMs). We report that, in contrast to other HRM-containing proteins, the cellular protein level and degradation rate of HO2 are independent of heme binding to the HRMs. Rather, under heme deficiency, loss of heme binding to the catalytic site destabilizes HO2. Consistently, a HO2 catalytic site variant that is unable to bind heme exhibits a constant low protein level and an enhanced protein degradation rate compared to the wild-type HO2. However, cellular heme overload does not affect HO2 stability. Finally, HO2 is degraded by the lysosome through chaperone-mediated autophagy, distinct from other HRM-containing proteins and HO1, which are degraded by the proteasome. These results reveal a novel aspect of HO2 regulation and deepen our understanding of HO2’s role in maintaining heme homeostasis, paving the way for future investigation into HO2’s pathophysiological role in heme deficiency response.

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Chaperone-mediated autophagy is involved in the execution of ferroptosis

Cited by 428 publications

References 69 publications

xCT Inhibition Increases Sensitivity to Vorinostat in a ROS-Dependent Manner

xCT Inhibition Increases Sensitivity to Vorinostat in a ROS-Dependent Manner

GPX4 at the Crossroads of Lipid Homeostasis and Ferroptosis

Absence of heme at the catalytic site of heme oxygenase-2 triggers its lysosomal degradation

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