Activated I-BAR IRSp53 clustering controls the formation of VASP-actin-based membrane protrusions

Area of Science:

• Cell Biology
• Biophysics
• Molecular Biology

Background:

• Filopodia are essential actin-rich cell structures involved in morphogenesis, motility, and cancer invasion.
• The precise mechanisms controlling filopodium initiation at the plasma membrane are not fully understood.

Purpose of the Study:

• To elucidate the mechanism of filopodium initiation driven by the membrane curvature sensor IRSp53.
• To investigate the role of IRSp53 self-assembly and its interaction with VASP in actin nucleation.

Main Methods:

• In cellulo, in vitro, and in silico experiments were conducted.
• In vitro reconstitution systems were used to study IRSp53 clustering and VASP recruitment.
• Membrane nanotubes were pulled from live cells to observe IRSp53 behavior in dynamic membrane regions.

Main Results:

• Full-length IRSp53 self-assembles into clusters on membranes, dependent on PIP2.
• IRSp53 clusters recruit VASP, leading to localized actin filament assembly and filopodia-like protrusion formation.
• IRSp53-mediated actin assembly occurs specifically in highly dynamic membrane regions, such as nanotubes.

Conclusions:

• IRSp53 acts as a membrane curvature sensor that regulates filopodium initiation.
• IRSp53's ability to sense curvature and recruit partners ensures spatiotemporal control over filopodium formation.
• This mechanism provides insights into cell motility and cancer invasion processes.