Department of Immunobiology, University of Lausanne, Epalinges, Switzerland.
EMBO J. 2024 Apr;43(7):1164-1186. doi: 10.1038/s44318-024-00055-y. Epub 2024 Feb 23.
Ferroptosis is a regulated form of necrotic cell death caused by iron-dependent accumulation of oxidized phospholipids in cellular membranes, culminating in plasma membrane rupture (PMR) and cell lysis. PMR is also a hallmark of other types of programmed necrosis, such as pyroptosis and necroptosis, where it is initiated by dedicated pore-forming cell death-executing factors. However, whether ferroptosis-associated PMR is also actively executed by proteins or driven by osmotic pressure remains unknown. Here, we investigate a potential ferroptosis role of ninjurin-1 (NINJ1), a recently identified executor of pyroptosis-associated PMR. We report that NINJ1 oligomerizes during ferroptosis, and that Ninj1-deficiency protects macrophages and fibroblasts from ferroptosis-associated PMR. Mechanistically, we find that NINJ1 is dispensable for the initial steps of ferroptosis, such as lipid peroxidation, channel-mediated calcium influx, and cell swelling. In contrast, NINJ1 is required for early loss of plasma membrane integrity, which precedes complete PMR. Furthermore, NINJ1 mediates the release of cytosolic proteins and danger-associated molecular pattern (DAMP) molecules from ferroptotic cells, suggesting that targeting NINJ1 could be a therapeutic option to reduce ferroptosis-associated inflammation.
铁死亡是一种由铁依赖性细胞内氧化磷脂积累引起的受调控的细胞坏死形式，最终导致质膜破裂（PMR）和细胞裂解。PMR 也是其他类型程序性细胞坏死（如细胞焦亡和坏死性凋亡）的特征，在这些细胞坏死中，PMR 是由专门的形成孔的细胞死亡执行因子引发的。然而，铁死亡相关的 PMR 是否也由蛋白质主动执行，或者是否由渗透压驱动，目前仍不清楚。在这里，我们研究了一种新发现的细胞焦亡相关 PMR 执行者——神经生长抑制因子 1（NINJ1）在铁死亡中的潜在作用。我们报告称，NINJ1 在铁死亡过程中会发生寡聚化，Ninj1 缺陷可保护巨噬细胞和成纤维细胞免受铁死亡相关 PMR 的影响。在机制上，我们发现 NINJ1 对于铁死亡的初始步骤（如脂质过氧化、通道介导的钙离子内流和细胞肿胀）是可有可无的。相比之下，NINJ1 对于早期质膜完整性的丧失是必需的，而这先于完全的 PMR。此外，NINJ1 介导了细胞质蛋白和危险相关分子模式（DAMP）分子从铁死亡细胞中的释放，这表明靶向 NINJ1 可能是减少铁死亡相关炎症的一种治疗选择。
