RNF217 regulates iron homeostasis through its E3 ubiquitin ligase activity by modulating ferroportin degradation

Jiang, Li; Wang, Jiaming; Wang, Kai; Wang, Hao; Wu, Qian; Cong, Yang; Yu, Yingying; Ni, Pu; Zhong, Yueyang; Song, Zijun; Xie, Enjun; Hu, Ronggui; Wang, Fudi

doi:10.1182/blood.2020008986

Cited by 80 publications

(46 citation statements)

References 73 publications

(45 reference statements)

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“…Ferroportin is the only known iron exporter in vertebrate cells, and cardiac iron overload, impaired heart function and a shortened lifespan have been observed in mice with early cardiomyocyte-specific deletion of the gene encoding ferroportin ( Fpn ) 29 , 30 . Hepcidin, a peptide hormone primarily synthesized in the liver, inhibits ferroportin via E3 ubiquitin protein ligase RNF217-mediated ubiquitination in the gut and spleen, which regulates iron absorption and iron recycling, respectively 31 , 32 . Genetic hepcidin deficiency causes the most severe form of systemic iron overload in both mice and humans 33 , 34 .…”

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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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%

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

et al. 2022

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“…Hepcidin inhibits cellular iron efflux by binding to and inducing the degradation of FPN. RNF217 was identified as a novel E3 ubiquitin ligase and was shown to play a role in mediating the degradation of FPN [ 30 ]. Notably, we previously showed that iron overload can directly induce ferroptosis in a variety of organs, including the liver and heart [ 14 , 26 , 31 ].…”

Section: Introductionmentioning

confidence: 99%

The multifaceted role of ferroptosis in liver disease

et al. 2022

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Ferroptosis is an iron-dependent form of non-apoptotic cell death characterized by excessive lipid peroxidation and associated with a plethora of pathological conditions in the liver. Emerging evidence supports the notion that dysregulated metabolic pathways and impaired iron homeostasis play a role in the progression of liver disease via ferroptosis. Although the molecular mechanisms by which ferroptosis causes disease are poorly understood, several ferroptosis-associated genes and pathways have been implicated in liver disease. Here, we review the physiological role of the liver in processing nutrients, our current understanding of iron metabolism, the characteristics of ferroptosis, and the mechanisms that regulate ferroptosis. In addition, we summarize the role of ferroptosis in the pathogenesis of liver disease, including liver injury, non-alcoholic steatohepatitis, liver fibrosis, liver cirrhosis, and hepatocellular carcinoma. Finally, we discuss the therapeutic potential of targeting ferroptosis for managing liver disease.

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“…It has been displayed that FPN1 is able to be phosphorylated and ubiquitinated (De Domenico et al, 2007); however, the corresponding E3 ubiquitin ligases and DUBs remain largely unknown. A recent study has shown that RNF217 mediates the ubiquitination and subsequent degradation of FPN1 (Jiang et al, 2021).…”

Section: Ubiquitination In Iron Metabolismmentioning

confidence: 99%

Regulation of Ferroptosis Pathway by Ubiquitination

Wang

et al. 2021

Front. Cell Dev. Biol.

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Ferroptosis is an iron-dependent form of programmed cell death, which plays crucial roles in tumorigenesis, ischemia–reperfusion injury and various human degenerative diseases. Ferroptosis is characterized by aberrant iron and lipid metabolisms. Mechanistically, excess of catalytic iron is capable of triggering lipid peroxidation followed by Fenton reaction to induce ferroptosis. The induction of ferroptosis can be inhibited by sufficient glutathione (GSH) synthesis via system Xc– transporter-mediated cystine uptake. Therefore, induction of ferroptosis by inhibition of cystine uptake or dampening of GSH synthesis has been considered as a novel strategy for cancer therapy, while reversal of ferroptotic effect is able to delay progression of diverse disorders, such as cardiopathy, steatohepatitis, and acute kidney injury. The ubiquitin (Ub)–proteasome pathway (UPP) dominates the majority of intracellular protein degradation by coupling Ub molecules to the lysine residues of protein substrate, which is subsequently recognized by the 26S proteasome for degradation. Ubiquitination is crucially involved in a variety of physiological and pathological processes. Modulation of ubiquitination system has been exhibited to be a potential strategy for cancer treatment. Currently, more and more emerged evidence has demonstrated that ubiquitous modification is involved in ferroptosis and dominates the vulnerability to ferroptosis in multiple types of cancer. In this review, we will summarize the current findings of ferroptosis surrounding the viewpoint of ubiquitination regulation. Furthermore, we also highlight the potential effect of ubiquitination modulation on the perspective of ferroptosis-targeted cancer therapy.

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RNF217 regulates iron homeostasis through its E3 ubiquitin ligase activity by modulating ferroportin degradation

Cited by 80 publications

References 73 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

The multifaceted role of ferroptosis in liver disease

Regulation of Ferroptosis Pathway by Ubiquitination

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