Journal Article

NINJ1 mediates plasma membrane rupture during lytic cell death

Li, Qingling, Modrusan, Zora, Payandeh, Jian, Xu, Min, Ulas, Gözde, Kornfeld, Opher S., Dixit, Vishva M., O’Rourke, Karen, Lee, Wyne P., Sagolla, Meredith, Lee, Bettina L., Zhang, Juan, Kayagaki, Nobuhiko, Yan, Donghong, McKenzie, Brent S., Sandoval, Wendy, Reja, Rohit, Cho, Vicky, Stowe, Irma B., Roose-Girma, Merone, Kang, Jing, Morris, Lucy X., Bertram, Edward M., Miosge, Lisa A., Webster, Joshua D., Goodnow, Christopher C., Andrews, T. Daniel

2021

Overview

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 response 1 – 3 . The underlying mechanism of PMR, however, is unknown. Here we show that the cell-surface NINJ1 protein 4 – 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.

• Publisher: Nature Publishing Group UK,Nature Publishing Group
• Subject: 13/109 / 13/2 / 13/21 / 13/51 / 13/95 / 14/1 / 14/19 / 14/63 / 38 / 38/1 / 38/109 / 38/39 / 42 / 631/250/256/2177 / 631/80/82/23 / 96/1 / 96/109 / 96/63 / 96/95 / Animals / Antiinfectives and antibacterials / Apoptosis / Cell Adhesion Molecules, Neuronal - chemistry / Cell Adhesion Molecules, Neuronal - genetics / Cell Adhesion Molecules, Neuronal - metabolism / Cell death / Cell Death - genetics / Cell Membrane - metabolism / Cell surface / Citrobacter / Cytokines / Damage patterns / Disintegration / Female / Genetic screening / HMGB1 protein / Humanities and Social Sciences / Humans / Infections / Inflammation / Intracellular / Macrophages / Male / Membranes / Mice / Morphology / Mortality / multidisciplinary / Mutation / Necrosis / Nerve Growth Factors - chemistry / Nerve Growth Factors - genetics / Nerve Growth Factors - metabolism / Oligomerization / Protein Multimerization / Proteins / Pyroptosis - genetics / Rupture / Rupturing / Science / Science (multidisciplinary)