The structure of erastin-bound xCT–4F2hc complex reveals molecular mechanisms underlying erastin-induced ferroptosis

Yan, Renhong; Xie, Enjun; Li, Yaning; Li, Jin; Zhang, Yuanyuan; Chi, Ximin; Hu, Xueping; Xu, Lei; Hou, Tingjun; Stockwell, Brent R.; Zhou, Qiang; Wang, Fudi

doi:10.1038/s41422-022-00642-w

Cited by 75 publications

(44 citation statements)

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“…System x c − exports intracellular glutamate and imports extracellular cystine at a 1:1 ratio; the newly imported cystine is then converted to cysteine in the cytosol via an NADPH-consuming reduction reaction 120 . The structure of human system x c − , which was resolved in 2020, clearly demonstrates the interaction between the two subunits at the extracellular interface and in the transmembrane region 121 – 123 . In addition, a well-resolved non-protein density was found in the intracellular vestibule of SCL7A11, to which an erastin molecule can bind 123 .…”

Section: Molecular and Metabolic Drivers Of Ferroptosismentioning

confidence: 99%

“…The structure of human system x c − , which was resolved in 2020, clearly demonstrates the interaction between the two subunits at the extracellular interface and in the transmembrane region 121 – 123 . In addition, a well-resolved non-protein density was found in the intracellular vestibule of SCL7A11, to which an erastin molecule can bind 123 . Therefore, inhibiting system x c − with erastin or its analogues can lead to the depletion of intracellular glutathione and trigger ferroptosis, suggesting a potentially viable strategy for antitumour therapies 2 , 124 .…”

Section: Molecular and Metabolic Drivers Of Ferroptosismentioning

confidence: 99%

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The molecular and metabolic landscape of iron and ferroptosis in cardiovascular disease

et al. 2022

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The maintenance of iron homeostasis is essential for proper cardiac function. A growing body of evidence suggests that iron imbalance is the common denominator in many subtypes of cardiovascular disease. In the past 10 years, ferroptosis, an iron-dependent form of regulated cell death, has become increasingly recognized as an important process that mediates the pathogenesis and progression of numerous cardiovascular diseases, including atherosclerosis, drug-induced heart failure, myocardial ischaemia–reperfusion injury, sepsis-induced cardiomyopathy, arrhythmia and diabetic cardiomyopathy. Therefore, a thorough understanding of the mechanisms involved in the regulation of iron metabolism and ferroptosis in cardiomyocytes might lead to improvements in disease management. In this Review, we summarize the relationship between the metabolic and molecular pathways of iron signalling and ferroptosis in the context of cardiovascular disease. We also discuss the potential targets of ferroptosis in the treatment of cardiovascular disease and describe the current limitations and future directions of these novel treatment targets.

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Section: Molecular and Metabolic Drivers Of Ferroptosismentioning

confidence: 99%

Section: Molecular and Metabolic Drivers Of Ferroptosismentioning

confidence: 99%

The molecular and metabolic landscape of iron and ferroptosis in cardiovascular disease

et al. 2022

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“…More recently, the structure of xCT/CD98 heterodimer has been obtained by Cryo-EM in both the apo (PDB:7P9U) and glutamate bound (PDB:7P9V) states ( Parker et al, 2021 ). The same experimental approach has been used by another group to obtain the structure of xCT/CD98 bound to erastin (PDB 7EPZ), a well-known ferroptosis inducer, shedding light on the molecular basis of ferroptosis ( Yan et al, 2022 ). Notwithstanding the huge efforts in deepening the knowledge of xCT structure, several functional and kinetic aspects of the transporter are still obscure and need to be addressed.…”

Section: Introductionmentioning

confidence: 99%

Production of recombinant human xCT (SLC7A11) and reconstitution in proteoliposomes for functional studies

et al. 2022

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The plasma membrane transporter xCT belongs to the SLC7 family and has the physiological role of mediating the exchange of glutamate and cystine across the cell plasma membrane, being crucial for redox control. The xCT protein forms a heterodimer with the ancillary protein CD98. Over the years, xCT became a hot pharmacological target due to the documented over-expression in virtually all human cancers, which rely on cystine availability for their progression. Notwithstanding, several unknown aspects of xCT biology still exist that require a suitable single protein experimental model, to be addressed. To this aim, the recombinant host Escherichia coli has been exploited to over-express the human isoform of xCT. In this widely used and low-cost system, the optimization for growth and protein production has been achieved by acting on the metabolic needs of the bacterial strains. Then, the His-tagged protein has been purified by Ni2+-chelating chromatography and reconstituted in proteoliposomes for transport activity assays. The expressed protein was in a folded/active state allowing functional and kinetic characterization. Interestingly, the features of the recombinant protein meet those of the native one extracted from intact cells, further confirming the suitability of E. coli as a host for the expression of human proteins. This study opens perspectives for elucidating other molecular aspects of xCT, as well as for studying the interaction with endogenous and exogenous compounds, relevant to human health.

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“…We found that BHPF induced tissue-specific ferroptosis and apoptosis in an m 6 A dependent manner, leading to cardiac and vascular developmental defects, respectively. Ferroptosis has recently emerged as a new form of programmed cell death (PCD) that is genetically, biologically and morphologically different from traditional forms of PCDs [23][24][25][26][27][28] . Interestingly, we identified that both BHPF-induced ferroptosis and apoptosis were controlled by the same m 6 A reader YTHDF2.…”

Section: Main Textmentioning

confidence: 99%

YTHDF2-mediated Distinct m6A Regulations Bifurcate Ferroptosis and Apoptosis in BHPF-induced Developmental Defects

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Lin

Zhan

et al. 2022

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N6-methyladenosine (m6A) is a critical regulator of RNA fate, but whether and how m6A executes its functions in different tissues remain largely obscure. Here we report YTHDF2 downregulation leading to various forms of tissue-specific programmed cell deaths (PCDs) upon fluorene-9-bisphenol (BHPF) exposure. Currently, bisphenol A (BPA) substitutes have been widely used in plastic manufacturing. Interrogating eight common BPA substitutes, we detected BHPF in 14% serum samples of pregnant women participants. In a zebrafish model, BHPF caused tissue-specific PCDs triggering cardiac and vascular developmental defects. Mechanistically, BHPF-mediated downregulation of YTHDF2 reduced YTHDF2-facilitated translation of m6A-gch1 for cardiomyocyte ferroptosis, and decreased YTHDF2-mediated m6A-sting1 decay for caudal vein plexus (CVP) apoptosis. Both YTHDF2-mediated distinct m6A regulations and context-dependent co-expression patterns of gch1/ythdf2 and tnfrsf1a/ythdf2 contributed to YTHDF2-mediated tissue-specific PCDs. Collectively, our findings demonstrate clear toxicity of BHPF during cardiovascular development via disrupting m6A/YTHDF2 regulatory axis and uncover a new layer of PCD regulation.

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The structure of erastin-bound xCT–4F2hc complex reveals molecular mechanisms underlying erastin-induced ferroptosis

Cited by 75 publications

References 15 publications

The molecular and metabolic landscape of iron and ferroptosis in cardiovascular disease

The molecular and metabolic landscape of iron and ferroptosis in cardiovascular disease

Production of recombinant human xCT (SLC7A11) and reconstitution in proteoliposomes for functional studies

YTHDF2-mediated Distinct m6A Regulations Bifurcate Ferroptosis and Apoptosis in BHPF-induced Developmental Defects

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