Adhesion energy controls lipid binding-mediated endocytosis

Raluca Groza, Kita Valerie Schmidt, Paul Markus Müller, Paolo Ronchi, Claire Schlack-Leigers, Ursula Neu, Dmytro Puchkov, Rumiana Dimova, Claudia Matthaeus, Justin Taraska, Thomas R. Weikl and Helge Ewers ()
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Raluca Groza: Freie Universität Berlin
Kita Valerie Schmidt: Freie Universität Berlin
Paul Markus Müller: Freie Universität Berlin
Paolo Ronchi: European Molecular Biology Laboratory
Claire Schlack-Leigers: Freie Universität Berlin
Ursula Neu: Freie Universität Berlin
Dmytro Puchkov: Leibniz-Forschungsinstitut für Molekulare Pharmakologie (FMP)
Rumiana Dimova: Potsdam Science Park
Claudia Matthaeus: National Institutes of Health
Justin Taraska: National Institutes of Health
Thomas R. Weikl: Potsdam Science Park
Helge Ewers: Freie Universität Berlin

Nature Communications, 2024, vol. 15, issue 1, 1-15

Abstract: Abstract Several bacterial toxins and viruses can deform membranes through multivalent binding to lipids for clathrin-independent endocytosis. However, it remains unclear, how membrane deformation and endocytic internalization are mechanistically linked. Here we show that many lipid-binding virions induce membrane deformation and clathrin-independent endocytosis, suggesting a common mechanism based on multivalent lipid binding by globular particles. We create a synthetic cellular system consisting of a lipid-anchored receptor in the form of GPI-anchored anti-GFP nanobodies and a multivalent globular binder exposing 180 regularly-spaced GFP molecules on its surface. We show that these globular, 40 nm diameter, particles bind to cells expressing the receptor, deform the plasma membrane upon adhesion and become endocytosed in a clathrin-independent manner. We explore the role of the membrane adhesion energy in endocytosis by using receptors with affinities varying over 7 orders of magnitude. Using this system, we find that once a threshold in adhesion energy is overcome to allow for membrane deformation, endocytosis occurs reliably. Multivalent, binding-induced membrane deformation by globular binders is thus sufficient for internalization to occur and we suggest it is the common, purely biophysical mechanism for lipid-binding mediated endocytosis of toxins and pathogens.

Date: 2024
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DOI: 10.1038/s41467-024-47109-7

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