Activating the NFE2L1-ubiquitin-proteasome system by DDI2 protects from ferroptosis.

IF 13.7 1区 生物学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY Cell Death and Differentiation Pub Date : 2024-10-09 DOI:10.1038/s41418-024-01398-z
Anahita Ofoghi, Stefan Kotschi, Imke L Lemmer, Daniel T Haas, Nienke Willemsen, Batoul Bayer, Anna S Jung, Sophie Möller, Stefanie Haberecht-Müller, Elke Krüger, Natalie Krahmer, Alexander Bartelt
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Abstract

Ferroptosis is an iron-dependent, non-apoptotic form of cell death initiated by oxidative stress and lipid peroxidation. Recent evidence has linked ferroptosis to the action of the transcription factor Nuclear factor erythroid-2 derived,-like-1 (NFE2L1). NFE2L1 regulates proteasome abundance in an adaptive fashion, maintaining protein quality control to secure cellular homeostasis, but the regulation of NFE2L1 during ferroptosis and the role of the ubiquitin-proteasome system (UPS) herein are still unclear. In the present study, using an unbiased proteomic approach charting the specific ubiquitylation sites, we show that induction of ferroptosis leads to recalibration of the UPS. RSL3-induced ferroptosis inhibits proteasome activity and leads to global hyperubiquitylation, which is linked to NFE2L1 activation. As NFE2L1 resides in the endoplasmic reticulum tethered to the membrane, it undergoes complex posttranslational modification steps to become active and induce the expression of proteasome subunit genes. We show that proteolytic cleavage of NFE2L1 by the aspartyl protease DNA-damage inducible 1 homolog 2 (DDI2) is a critical step for the ferroptosis-induced feed-back loop of proteasome function. Cells lacking DDI2 cannot activate NFE2L1 in response to RSL3 and show global hyperubiquitylation. Genetic or chemical induction of ferroptosis in cells with a disrupted DDI2-NFE2L1 pathway diminishes proteasomal activity and promotes cell death. Also, treating cells with the clinical drug nelfinavir, which inhibits DDI2, sensitized cells to ferroptosis. In conclusion, our results provide new insight into the importance of the UPS in ferroptosis and highlight the role of the DDI2-NFE2L1 as a potential therapeutic target. Manipulating DDI2-NFE2L1 activity through chemical inhibition might help sensitizing cells to ferroptosis, thus enhancing existing cancer therapies.

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DDI2激活NFE2L1-泛素-蛋白酶体系统可防止铁变态反应。
铁凋亡是一种由氧化应激和脂质过氧化引发的铁依赖性、非凋亡性细胞死亡形式。最近的证据表明,铁凋亡与转录因子核因子红细胞-2衍生样-1(NFE2L1)的作用有关。NFE2L1 以适应性方式调节蛋白酶体的丰度,维持蛋白质质量控制以确保细胞稳态,但 NFE2L1 在铁变态反应过程中的调节作用以及泛素-蛋白酶体系统(UPS)在其中的作用仍不清楚。在本研究中,我们采用无偏见的蛋白质组学方法绘制了特定泛素化位点图,结果表明诱导铁变态反应会导致 UPS 的重新校准。RSL3 诱导的铁变态反应抑制了蛋白酶体的活性,导致全局泛素化过度,而泛素化过度与 NFE2L1 的激活有关。由于 NFE2L1 位于内质网中并与膜相连,因此它需要经过复杂的翻译后修饰步骤才能变得活跃并诱导蛋白酶体亚基基因的表达。我们的研究表明,天冬氨酰蛋白酶 DNA-damage inducible 1 homolog 2(DDI2)对 NFE2L1 的蛋白水解是铁变态反应诱导蛋白酶体功能回馈环的关键步骤。缺乏 DDI2 的细胞不能激活 NFE2L1 对 RSL3 作出反应,并表现出整体泛素化过度。在 DDI2-NFE2L1 通路被破坏的细胞中,遗传或化学诱导的铁突变会降低蛋白酶体的活性并促进细胞死亡。此外,用抑制 DDI2 的临床药物奈非那韦处理细胞,也会使细胞对铁蛋白沉积敏感。总之,我们的研究结果为了解 UPS 在铁蛋白沉积过程中的重要性提供了新的视角,并突出了 DDI2-NFE2L1 作为潜在治疗靶点的作用。通过化学抑制操纵 DDI2-NFE2L1 的活性可能有助于使细胞对铁变态反应敏感,从而增强现有的癌症疗法。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
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来源期刊
Cell Death and Differentiation
Cell Death and Differentiation 生物-生化与分子生物学
CiteScore
24.70
自引率
1.60%
发文量
181
审稿时长
3 months
期刊介绍: Mission, vision and values of Cell Death & Differentiation: To devote itself to scientific excellence in the field of cell biology, molecular biology, and biochemistry of cell death and disease. To provide a unified forum for scientists and clinical researchers It is committed to the rapid publication of high quality original papers relating to these subjects, together with topical, usually solicited, reviews, meeting reports, editorial correspondence and occasional commentaries on controversial and scientifically informative issues.
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