NINJ1 induces plasma membrane rupture and DAMP release during ferroptosis
Ontology highlight
ABSTRACT:
ORGANISM(S): Homo sapiens (human) Mus musculus (mouse)
SUBMITTER:
PROVIDER: S-BSST1254 | biostudies-other |
REPOSITORIES: biostudies-other
Similar Datasets
Project description:Ferroptosis is a regulated form of necrotic cell death caused by an iron-dependent accumulation of oxidized phospholipids in cellular membranes, which culminates 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 executors. Yet, whether ferroptosis-associated PMR is actively executed by a protein or driven by osmotic pressure remains unknown. Here, we investigated the role of ninjurin-1 (NINJ1), the recently identified executor of pyroptosis-associated PMR, in ferroptosis. We report that during ferroptosis NINJ1 oligomerizes and that Ninj1-deficiency protects macrophages and fibroblasts from ferroptosis-associated PMR. Mechanistically, we find that NINJ1 is dispensable for the early steps of ferroptosis, such as lipid peroxidation, channel-mediated calcium influx and cell swelling. By contrast, NINJ1 is required for early loss of plasma membrane integrity, an event that precedes complete PMR. Furthermore, NINJ1 mediates the release of cytosolic proteins and danger-associated molecular patterns (DAMPs) from ferroptotic cells, suggesting that targeting NINJ1 could be a therapeutic option to reduce ferroptosis-associated inflammation.
2024-02-15 | PXD047622 | Pride
Project description: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. Plasma membrane rupture 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.
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