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^1,2,3. The underlying mechanism of PMR, however, is unknown. Here we show that the cell-surface NINJ1 protein^4,5,6,7,8, 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.

质膜破裂 (PMR) 是裂解性细胞死亡的最后灾难性事件。PMR 释放细胞内分子，称为损伤相关分子模式 (DAMP)，传播炎症反应^1,2,3。然而，PMR 的潜在机制尚不清楚。在这里，我们显示包含两个跨膜区域的细胞表面 NINJ1 蛋白^4,5,6,7,8在 PMR 的诱导中具有重要作用。随机诱变小鼠的正向遗传筛选将 NINJ1 与 PMR 联系起来。Ninj1 ^-/-巨噬细胞表现出 PMR 受损以响应多种细胞焦亡、坏死和凋亡细胞死亡诱导剂，并且无法释放大量细胞内蛋白，包括 HMGB1（已知的 DAMP）和 LDH（PMR 的标准测量值）。Ninj1 ^–/–巨噬细胞死亡，但具有独特且持久的气球状形态，这归因于气泡状疝的崩解缺陷。Ninj1 ^–/–小鼠比野生型小鼠更容易感染柠檬酸杆菌，这表明 PMR 在抗菌宿主防御中发挥作用。从机制上讲，NINJ1 使用进化上保守的细胞外结构域进行寡聚化和随后的 PMR。NINJ1 作为 PMR 介体的发现推翻了长期以来认为与细胞死亡相关的 PMR 是被动事件的观点。