Critical Role of Lipid Scramblase TMEM16F in Phosphatidylserine Exposure and Repair of Plasma Membrane after Pore Formation

Plasma membrane damage and cell death during processes such as necroptosis and apoptosis result from cues originating intracellularly. However, death caused by pore-forming agents, like bacterial toxins or complement, is due to direct external injury to the plasma membrane. To prevent death, the plasma membrane has an intrinsic repair ability. Here, we found that repair triggered by pore-forming agents involved TMEM16F, a calcium-activated lipid scramblase also mutated in Scott’s syndrome. Upon pore formation and the subsequent influx of intracellular calcium, TMEM16F induced rapid “lipid scrambling” in the plasma membrane. This response was accompanied by membrane blebbing, extracellular vesicle release, preserved membrane integrity, and increased cell viability. TMEM16F-deficient mice exhibited compromised control of infection by Listeria monocytogenes associated with a greater sensitivity of neutrophils to the pore-forming Listeria toxin listeriolysin O (LLO). Thus, the lipid scramblase TMEM16F is critical for plasma membrane repair after injury by pore-forming agents. [Display omitted] •Pore-forming agents evoke calcium-dependent lipid scrambling in the plasma membrane•This effect promotes plasma membrane repair and is mediated by lipid scramblase TMEM16F•TMEM16F induces repair by facilitating release of extracellular vesicles•TMEM16F-deficient mice display greater susceptibility to Listeria monocytogenes Pore-forming agents like bacterial toxins or complement kill cells by attacking the plasma membrane. Wu et al. show that the calcium-activated lipid scramblase TMEM16F promotes plasma membrane repair after pore formation by enhancing membrane fluidity and facilitating release of extracellular vesicles containing damaged membranes.