NINJ1 mediates plasma membrane rupture during lytic cell death

By N. Kayagaki, Opher S. Kornfeld, Bettina L. Lee, Irma B. Stowe, K. O’Rourke, Qingling Li, W. Sandoval, D. Yan, Jing Kang, M. Xu and 17 more. Nature, 2020

675 citations recorded by the source corpus.

Plasma membrane rupture (PMR) is the final cataclysmic event in lytic cell death. PMR releases intracellular molecules known as damage-associated molecular patterns (DAMPs) that propagate the inflammatory response1–3. The underlying mechanism of PMR, however, is unknown. Here we show that the cell-surface NINJ1 protein4–8, which contains two transmembrane regions, has an essential role in the induction of PMR. A forward-genetic screen of randomly mutagenized mice linked NINJ1 to PMR. Ninj1−/− macrophages exhibited impaired PMR in response to diverse inducers of pyroptotic, necrotic and apoptotic cell death, and were unable to release numerous intracellular proteins including HMGB1 (a known DAMP) and LDH (a standard measure of PMR). Ninj1–/– macrophages died, but with a distinctive and persistent ballooned morphology, attributable to defective disintegration of bubble-like herniations. Ninj1–/– mice were more susceptible than wild-type mice to infection with Citrobacter rodentium, which suggests a role for PMR in anti-bacterial host defence. Mechanistically, NINJ1 used an evolutionarily conserved extracellular domain for oligomerization and subsequent PMR. The discovery of NINJ1 as a mediator of PMR overturns the long-held idea that cell death-related PMR is a passive event. The small transmembrane protein NINJ1 promotes plasma membrane rupture in lytic cell death associated with pyroptosis, necrosis and apoptosis.

Subfields: Endocrinology, Epidemiology, Molecular Biology

View Paper: https://www.semanticscholar.org/paper/a5ecdcaa39c58e93fdd1c7d2dd5b483c51f118f9

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In Endocrinology

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Citations in the corpus

Inflammation and aging: signaling pathways and intervention therapies (2023, background): “4).(242) These findings suggest an age-associated dysregulation of necroptosis signaling, indicating a potential role for necroptosis in aging and related pathologies.”
The cell biology of ferroptosis (2024, neutral): “11,12).”
Molecular mechanisms of cell death in neurological diseases (2021, background): “However, unlike necroptosis, necrosis lacks a defined core cellular signalling machinery but Ninj1 has recently been identified as being critical for the rupture of the plasma membrane [140].”
Pyroptosis in inflammatory diseases and cancer (2022, background): “Cell-surface protein NINJ1 has an essential role in the induction of plasma membrane rupture, which is responsible for releasing intracellular molecules that propagate the inflammatory response [14].”
From pyroptosis, apoptosis and necroptosis to PANoptosis: A mechanistic compendium of programmed cell death pathways (2021, background): “…found that the surface molecule NINJ1 is important for rupture in necroptosis as well as pyroptosis and apoptosis to mediate the release of large proteins, such as LDH and HMGB1 [79], and future studies will be required to fully elucidate the mechanism of pore formation and plasma membrane rupture.”
A guide to cell death pathways (2023, positive): “NINJ1 may be normally involved in the maintenance of functional synapses as Ninj1 -null mice exhibit compulsive grooming-induced hair loss and self-made lesions as well as increased anxiety-like behaviours 128 .”