Adhesion energy controls lipid binding-mediated endocytosis.

Area of Science:

• Cell biology
• Biophysics
• Molecular mechanisms of endocytosis

Background:

• Bacterial toxins and viruses utilize multivalent lipid binding to deform cell membranes, facilitating clathrin-independent endocytosis.
• The precise mechanistic link between membrane deformation and subsequent endocytic internalization remains incompletely understood.

Purpose of the Study:

• To investigate the mechanistic link between membrane deformation and clathrin-independent endocytosis induced by multivalent lipid binding.
• To determine if binding-induced membrane deformation by globular particles is sufficient for cellular internalization.

Main Methods:

• Development of a synthetic cellular system using lipid-anchored receptors (GPI-anchored anti-GFP nanobodies) and a multivalent globular binder (40 nm particles with 180 GFP molecules).
• Quantitative analysis of membrane deformation and endocytosis triggered by varying receptor-ligand affinities (spanning 7 orders of magnitude).
• Observation of particle adhesion, membrane deformation, and clathrin-independent endocytosis in the synthetic system.

Main Results:

• The synthetic globular particles successfully bind to cells, induce significant plasma membrane deformation upon adhesion, and are internalized via clathrin-independent endocytosis.
• A clear threshold in membrane adhesion energy was identified, beyond which membrane deformation reliably leads to endocytosis.
• Multivalent binding by globular particles is demonstrated to be sufficient for inducing membrane deformation and subsequent internalization.

Conclusions:

• Binding-induced membrane deformation by multivalent globular particles is a sufficient mechanism for clathrin-independent endocytosis.
• This biophysical mechanism likely underlies the endocytosis of various lipid-binding toxins and pathogens.
• The study elucidates a common pathway for pathogen and toxin entry mediated by membrane interaction.