Lipid scrambling via TMEM16F mediates the formation and release of extracellular vesicles

Area of Science:

• Cell Biology
• Biochemistry
• Membrane Dynamics

Background:

• Programmed cell death pathways are crucial for tissue development and homeostasis.
• Apoptotic cells release membrane fragments, including apoptotic bodies and smaller vesicles.
• Mechanisms of apoptotic body formation are known, but vesicle biogenesis is less understood.

Purpose of the Study:

• To investigate the role of lipid scrambling in vesiculation during programmed cell death.
• To determine if lipid scrambling alone can induce vesicle release independently of other apoptotic signaling events.

Main Methods:

• Utilized an inducible, active form of TMEM16F to induce plasmalemmal lipid scrambling.
• Analyzed vesicle release, cytosolic calcium levels, and submembrane cytoskeleton integrity.
• Examined lipid distribution and membrane curvature changes in the plasma membrane.

Main Results:

• Plasmalemmal lipid scrambling induced the release of apoptotic-like vesicles without altering cytosolic calcium or cytoskeleton.
• Scrambled membranes showed lipid segregation and cholesterol redistribution to the inner leaflet.
• Accumulation of phosphatidylethanolamine (PE) and clustering of raft components induced membrane curvature, facilitating vesicle scission.

Conclusions:

• Lipid scrambling is sufficient to induce vesiculation analogous to that seen in apoptotic cells.
• TMEM16F-mediated lipid scrambling drives the formation of outward and inward membrane curvature.
• This process facilitates the detachment of vesicles from the plasma membrane, contributing to cell death morphology.