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Prominin2 Drives Ferroptosis Resistance by Stimulating Iron Export.
Developmental Cell ( IF 10.7 ) Pub Date : 2019-11-14 , DOI: 10.1016/j.devcel.2019.10.007 Caitlin W Brown 1 , John J Amante 1 , Peter Chhoy 1 , Ameer L Elaimy 1 , Haibo Liu 1 , Lihua Julie Zhu 1 , Christina E Baer 2 , Scott J Dixon 3 , Arthur M Mercurio 1
Developmental Cell ( IF 10.7 ) Pub Date : 2019-11-14 , DOI: 10.1016/j.devcel.2019.10.007 Caitlin W Brown 1 , John J Amante 1 , Peter Chhoy 1 , Ameer L Elaimy 1 , Haibo Liu 1 , Lihua Julie Zhu 1 , Christina E Baer 2 , Scott J Dixon 3 , Arthur M Mercurio 1
Affiliation
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Ferroptosis, regulated cell death characterized by the iron-dependent accumulation of lethal lipid reactive oxygen species, contributes to tissue homeostasis and numerous pathologies, and it may be exploited for therapy. Cells differ in their sensitivity to ferroptosis, however, and a key challenge is to understand mechanisms that contribute to resistance. Using RNA-seq to identify genes that contribute to ferroptosis resistance, we discovered that pro-ferroptotic stimuli, including inhibition of the lipid hydroperoxidase GPX4 and detachment from the extracellular matrix, induce expression of prominin2, a pentaspanin protein implicated in regulation of lipid dynamics. Prominin2 facilitates ferroptosis resistance in mammary epithelial and breast carcinoma cells. Mechanistically, prominin2 promotes the formation of ferritin-containing multivesicular bodies (MVBs) and exosomes that transport iron out of the cell, inhibiting ferroptosis. These findings reveal that ferroptosis resistance can be driven by a prominin2-MVB-exosome-ferritin pathway and have broad implications for iron homeostasis, intracellular trafficking, and cancer.
中文翻译：
Prominin2 通过刺激铁输出来驱动铁死亡抵抗。
铁死亡是一种受调节的细胞死亡，其特征是致命脂质活性氧的铁依赖性积累，有助于组织稳态和许多病理学，并且可用于治疗。然而，细胞对铁死亡的敏感性有所不同，一个关键的挑战是了解导致耐药性的机制。使用RNA-seq来鉴定有助于铁死亡抗性的基因，我们发现促铁死亡刺激，包括抑制脂质氢过氧化物酶GPX4和从细胞外基质脱离，诱导prominin2的表达，prominin2是一种参与脂质动态调节的pentaspanin蛋白。Prominin2 促进乳腺上皮细胞和乳腺癌细胞的铁死亡抵抗。从机制上讲，prominin2 促进含铁蛋白的多泡体 (MVB) 和外泌体的形成，将铁转运出细胞，从而抑制铁死亡。这些发现表明，铁死亡抵抗可以由 prominin2-MVB-外泌体-铁蛋白途径驱动，并且对铁稳态、细胞内运输和癌症具有广泛的影响。
更新日期：2019-11-14
中文翻译：
Prominin2 通过刺激铁输出来驱动铁死亡抵抗。
铁死亡是一种受调节的细胞死亡，其特征是致命脂质活性氧的铁依赖性积累，有助于组织稳态和许多病理学，并且可用于治疗。然而，细胞对铁死亡的敏感性有所不同，一个关键的挑战是了解导致耐药性的机制。使用RNA-seq来鉴定有助于铁死亡抗性的基因，我们发现促铁死亡刺激，包括抑制脂质氢过氧化物酶GPX4和从细胞外基质脱离，诱导prominin2的表达，prominin2是一种参与脂质动态调节的pentaspanin蛋白。Prominin2 促进乳腺上皮细胞和乳腺癌细胞的铁死亡抵抗。从机制上讲，prominin2 促进含铁蛋白的多泡体 (MVB) 和外泌体的形成，将铁转运出细胞，从而抑制铁死亡。这些发现表明，铁死亡抵抗可以由 prominin2-MVB-外泌体-铁蛋白途径驱动，并且对铁稳态、细胞内运输和癌症具有广泛的影响。
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