BPS2026 – Tension-mediated feedback between the cortex and phospholipid scramblases underlies plasma membrane blebbing

Asymmetry between plasma membrane (PM) leaflets is a fundamental property of all cells, yet it is lost during rapid membrane expansion and blebbing, processes involved in apoptosis, amoeboid migration, and immune cell evasion. Calcium influx activates the lipid scramblase TMEM16F, exposing phosphatidylserine, while calcium-dependent proteases detach the PM from the actin cortex. While both processes are essential for bleb formation, their relationship remains poorly defined. Using a combination of live-cell imaging approaches, we show that scrambling and cortex detachment demonstrate a positive feedback loop. Detachment precedes scrambling, lowers PM tension, and spatially restricts scrambling to regions uncoupled from the cortex. Disrupting PM-cortex interactions promotes scrambling via reductions in membrane tension, while stabilization prevents both scrambling and blebbing. Scrambling, in turn, promotes propagation of cortex detachment, a process that is lost in cells lacking TMEM16F. In wild-type cells, scrambling permits the propagation of membrane-cortex uncoupling, allowing for global bleb expansion. Our findings demonstrate a reciprocal relationship between cortex detachment and lipid scrambling governed by membrane tension. Cortex detachment relieves mechanical constraints on the PM, permitting lipid scrambling, while scrambling feeds back to propagate detachment. This coordinated response integrates mechanical and biochemical signals, enabling rapid membrane remodeling that preserves cell viability during bleb formation.