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Ramos, Saray; Hartenian, Ella; Santos, José Carlos; Walch, Philipp; Broz, Petr
The EMBO journal, 04/2024, Letnik: 43, Številka: 7Journal Article
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. Synopsis Induction of ferroptosis by lipid peroxidation can lead to plasma membrane rupture, but the mediators of this rupture are unknown. This study identifies Ninjurin-1 (NINJ1) as the executor of plasma membrane permeabilization in ferroptotic macrophages and fibroblasts. Ferroptosis induction leads to NINJ1 activation and oligomerization in macrophages and fibroblasts. NINJ1 activation occurs downstream of lipid peroxidation and calcium influx, the first steps of ferroptosis. NINJ1 activation triggers the last steps of ferroptosis, i.e., loss of membrane integrity and rupture. NINJ1 controls the release of cytosolic proteins and danger-associated molecular pattern molecules from ferroptotic cells. Ninjurin-1 (NINJ1) oligomerizes and mediates loss of plasma membrane integrity as well as plasma membrane rupture in ferroptotic cells.
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JCR | SNIP | JCR | SNIP | JCR | SNIP | JCR | SNIP |
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