NINJ1 regulates plasma membrane fragility under mechanical strain

作者：Yunfeng Zhu, Fang Xiao, Yiling Wang, Yufang Wang, Jialin Li, Dongmei Zhong, Zhilei Huang, Miao Yu, Zhirong Wang, Joshua Barbara, Christopher Plunkett, Mengxue Zeng, Yiyan Song, Tian Tan, Rui Zhang, Kunyuan Xu, Zhongxing Wang, Changjie Cai, Xiangdong Guan, Scott Hammack, Liang Zhang, Zheng Shi, Fu-Li Xiang, Feng Shao, Jie Xu · 发表于：Nature · 年份：2025 · 被引用次数：55 · 研究领域：Inflammasome and immune disorders、Erythrocyte Function and Pathophysiology、Ion channel regulation and function

Plasma membrane integrity is vital for nearly all aspects of cell functioning 1 . Mechanical forces can cause plasma membrane damage 2 , but it is not known whether there are large molecules that regulate plasma membrane integrity under mechanical strain. Here we constructed a 384-well cellular stretch system that delivers precise, reproducible strain to cultured cells. Using the system, we screened 10,843 siRNAs targeting 2,726 multi-pass transmembrane proteins for strain-induced membrane permeability changes. The screen identified NINJ1, a protein recently proposed to regulate pyroptosis and other lytic cell death 3,4 , as the top hit. We demonstrate that NINJ1 is a critical regulator for mechanical strain-induced plasma membrane rupture (PMR), without the need of stimulating any cell death programs. NINJ1 level on the plasma membrane is inversely correlated to the amount of force required to rupture the membrane. In the pyroptosis context, NINJ1 on its own is not sufficient to fully rupture the membrane, and additional mechanical force is required for full PMR. Our work establishes that NINJ1 functions as a bona fide determinant of membrane biomechanical properties. Our study also suggests that PMR across tissues of distinct mechanical microenvironments is subjected to fine tuning by differences in NINJ1 expression and external forces.