NINJ1 regulates ferroptosis via xCT antiporter interaction and CoA modulation.

IF 8.1 1区 生物学 Q1 CELL BIOLOGY Cell Death & Disease Pub Date : 2024-10-18 DOI:10.1038/s41419-024-07135-1
Ssu-Yu Chen, Jianli Wu, Yubin Chen, Ya-En Wang, Yasaman Setayeshpour, Chiara Federico, Alexander A Mestre, Chao-Chieh Lin, Jen-Tsan Chi
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Abstract

Ninjurin-1 (NINJ1), initially identified as a stress-induced protein in neurons, recently emerged as a key mediator of plasma membrane rupture (PMR) during apoptosis, necrosis, and pyroptosis. However, its involvement in ferroptosis is less well elucidated. Here, we demonstrate that NINJ1 also plays a crucial role in ferroptosis, but through a distinct mechanism. NINJ1 knockdown significantly protected cancer cells against ferroptosis induced only by xCT inhibitors but no other classes of ferroptosis-inducing compounds (FINs). Glycine, known to inhibit canonical NINJ1-mediated membrane rupture in other cell deaths, had no impact on ferroptosis. A compound screen revealed that the ferroptosis protective effect caused by NINJ1 knockdown can be abolished by pantothenate kinase inhibitor (PANKi), buthionine sulfoximine (BSO), and diethylmaleate (DEM). These results suggest that this ferroptosis protection is mediated via Coenzyme A (CoA) and glutathione (GSH), both of which were found to be elevated upon NINJ1 knockdown. Furthermore, we discovered that NINJ1 interacts with the xCT antiporter, which is responsible for cystine uptake for the biosynthesis of CoA and GSH. The removal of NINJ1 increased xCT levels and stability, enhancing cystine uptake and thereby providing protection against ferroptosis. Conversely, NINJ1 overexpression reduced xCT levels and sensitized ferroptosis. These findings reveal that NINJ1 regulates ferroptosis via a non-canonical mechanism, distinct from other regulated cell deaths.

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NINJ1 通过 xCT 反转运体相互作用和 CoA 调节来调控铁虹吸。
Ninjurin-1(NINJ1)最初被确定为神经元中的一种应激诱导蛋白,最近又被认为是细胞凋亡、坏死和热凋亡过程中质膜破裂(PMR)的关键介质。然而,它在铁凋亡中的参与还不太清楚。在这里,我们证明了 NINJ1 在铁凋亡中也起着至关重要的作用,但却是通过一种不同的机制。NINJ1 基因敲除可显著保护癌细胞免受 xCT 抑制剂诱导的铁嗜酸沉着,而其他类型的铁嗜酸沉着诱导化合物(FINs)则不会诱导铁嗜酸沉着。已知甘氨酸能抑制其他细胞死亡过程中由 NINJ1 介导的膜破裂,但甘氨酸对铁突变没有影响。通过化合物筛选发现,泛酸激酶抑制剂(PANKi)、丁硫氨酸亚砜亚胺(BSO)和马来酸二乙酯(DEM)可以取消 NINJ1 敲除引起的铁突变保护效应。这些结果表明,这种铁突变保护作用是通过辅酶 A(CoA)和谷胱甘肽(GSH)介导的。此外,我们还发现 NINJ1 与 xCT 反转运体相互作用,后者负责胱氨酸的吸收,以促进 CoA 和 GSH 的生物合成。去除 NINJ1 会增加 xCT 的水平和稳定性,加强胱氨酸的摄取,从而提供对铁卟啉中毒的保护。相反,NINJ1 的过表达会降低 xCT 的水平,并使铁变态反应敏感化。这些发现揭示了 NINJ1 通过一种非经典机制调控铁突变,不同于其他调控细胞死亡的机制。
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来源期刊
Cell Death & Disease
Cell Death & Disease CELL BIOLOGY-
CiteScore
15.10
自引率
2.20%
发文量
935
审稿时长
2 months
期刊介绍: Brought to readers by the editorial team of Cell Death & Differentiation, Cell Death & Disease is an online peer-reviewed journal specializing in translational cell death research. It covers a wide range of topics in experimental and internal medicine, including cancer, immunity, neuroscience, and now cancer metabolism. Cell Death & Disease seeks to encompass the breadth of translational implications of cell death, and topics of particular concentration will include, but are not limited to, the following: Experimental medicine Cancer Immunity Internal medicine Neuroscience Cancer metabolism
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