Sahoo Bibekananda, Mou Zongjun, Liu Wei, Dubyak George, Dai Xinghong
Department of Physiology and Biophysics, Case Western Reserve University, Cleveland, OH 44106, USA.
Department of Physiology and Biophysics, Case Western Reserve University, Cleveland, OH 44106, USA.
Cell. 2025 Jan 23;188(2):292-302.e11. doi: 10.1016/j.cell.2024.11.021. Epub 2024 Dec 11.
Ninjurin-1 (NINJ1) is an active executioner of plasma membrane rupture (PMR), a process previously thought to be a passive osmotic lysis event in lytic cell death. Ninjurin-2 (NINJ2) is a close paralog of NINJ1 but cannot mediate PMR. Using cryogenic electron microscopy (cryo-EM), we show that NINJ1 and NINJ2 both assemble into linear filaments that are hydrophobic on one side but hydrophilic on the other. This structural feature and other evidence point to a PMR mechanism by which NINJ1 filaments wrap around and solubilize membrane fragments and, less frequently, form pores in the plasma membrane. In contrast to the straight NINJ1 filament, the NINJ2 filament is curved toward the intracellular space, preventing its circularization or even assembly on a relatively flat membrane to mediate PMR. Mutagenesis studies further demonstrate that the NINJ2 filament curvature is induced by strong association with lipids, particularly a cholesterol molecule, at the cytoplasmic leaflet of the lipid bilayer.
Ninjurin-1（NINJ1）是质膜破裂（PMR）的一个活跃执行者，质膜破裂这一过程以前被认为是溶解性细胞死亡中被动的渗透性裂解事件。Ninjurin-2（NINJ2）是NINJ1的紧密旁系同源物，但不能介导质膜破裂。利用低温电子显微镜（cryo-EM），我们发现NINJ1和NINJ2都组装成线性细丝，这些细丝一侧疏水而另一侧亲水。这一结构特征和其他证据指向一种质膜破裂机制，即NINJ1细丝缠绕并溶解膜碎片，并且较少情况下在质膜中形成孔。与笔直的NINJ1细丝不同，NINJ2细丝向细胞内空间弯曲，阻止其环化甚至在相对平坦的膜上组装以介导质膜破裂。诱变研究进一步表明，NINJ2细丝的弯曲是由与脂质，特别是脂质双分子层细胞质小叶处的一个胆固醇分子的强烈结合所诱导的。
