Abstract
Extracellular vesicles (EVs) are fundamental for proper physiological functioning of multicellular organisms. By shuttling nucleic acids and proteins between cells, EVs regulate a plethora of cellular processes, especially those involved in immune signalling. However, the mechanistic understanding concerning the biophysical principles underlying EV-based communication is still incomplete. Towards holistic understanding, particular mechanisms explaining why and when cells apply EV-based communication and how protein-based signalling is promoted by EV surfaces are sought. Here, the authors study vesicle-induced receptor sequestration (VIRS) as a universal mechanism augmenting the signalling potency of proteins presented on EV-membranes. By bottom-up reconstitution of synthetic EVs, the authors show that immobilization of the receptor ligands FasL and RANK on EV-like vesicles, increases their signalling potential by more than 100-fold compared to their soluble forms. Moreover, the authors perform diffusion simulations within immunological synapses to compare receptor activation between soluble and EV-presented proteins. By this the authors propose vesicle-triggered local clustering of membrane receptors as the principle structural mechanism underlying EV-based protein presentation. The authors conclude that EVs act as extracellular templates promoting the local aggregation of membrane receptors at the EV contact site, thereby fostering inter-protein interactions. The results uncover a potentially universal mechanism explaining the unique structural profit of EV-based intercellular signalling.
| Original language | English |
|---|---|
| Article number | 2200201 |
| Journal | Advanced Science |
| Volume | 9 |
| Issue number | 13 |
| Early online date | 1 Mar 2022 |
| DOIs | |
| Publication status | Published - 5 Mar 2022 |
Bibliographical note
Funding Information:O.S., J.E.H.B., and J.F. contributed equally to this work. The authors acknowledge funding from the Federal Ministry of Education and Research of Germany, Grant Agreement no. 13XP5073A, PolyAntiBak and the MaxSynBio Consortium, which is jointly funded by the Federal Ministry of Education and Research of Germany and the Max Planck Society. The authors also acknowledge the support from the German Science Foundation SFB 1129 and the Deutsche Forschungsgemeinschaft (DFG, German Research Foundation) under Germany's Excellence Strategy via the Excellence Cluster 3D Matter Made to Order (EXC‐2082/1 – 390761711). They also acknowledge the support from the Volkswagen Stiftung (priority call “Life?”). The author would like to thank Ulrike Mersdorf for help with cryoTEM experiments and Stefan Kallenberger (Health Data Science Unit, University Hospital Heidelberg) for helpful discussions. O.S. acknowledges support from the Heidelberg Bioscience International Graduate School, the Max Planck School Matter to Life and the Joachim Herz Foundation. J.P.S. is the Weston Visiting Professor at the Weizmann Institute of Science and part of the excellence cluster CellNetworks at the University of Heidelberg. O.S. is the Meurer Visiting Professor at the University of Bristol. J.F. acknowledges continuous support from Kerstin Göpfrich (MPI Medical Research). The Max Planck Society is appreciated for its general support.
Funding Information:
O.S., J.E.H.B., and J.F. contributed equally to this work. The authors acknowledge funding from the Federal Ministry of Education and Research of Germany, Grant Agreement no. 13XP5073A, PolyAntiBak and the MaxSynBio Consortium, which is jointly funded by the Federal Ministry of Education and Research of Germany and the Max Planck Society. The authors also acknowledge the support from the German Science Foundation SFB 1129 and the Deutsche Forschungsgemeinschaft (DFG, German Research Foundation) under Germany's Excellence Strategy via the Excellence Cluster 3D Matter Made to Order (EXC-2082/1 – 390761711). They also acknowledge the support from the Volkswagen Stiftung (priority call “Life?”). The author would like to thank Ulrike Mersdorf for help with cryoTEM experiments and Stefan Kallenberger (Health Data Science Unit, University Hospital Heidelberg) for helpful discussions. O.S. acknowledges support from the Heidelberg Bioscience International Graduate School, the Max Planck School Matter to Life and the Joachim Herz Foundation. J.P.S. is the Weston Visiting Professor at the Weizmann Institute of Science and part of the excellence cluster CellNetworks at the University of Heidelberg. O.S. is the Meurer Visiting Professor at the University of Bristol. J.F. acknowledges continuous support from Kerstin Göpfrich (MPI Medical Research). The Max Planck Society is appreciated for its general support. Open Access funding enabled and organized by Projekt DEAL. Correction added on April 11, 2022, after first online publication: Projekt Deal funding statement has been added.
Publisher Copyright:
© 2022 The Authors. Advanced Science published by Wiley-VCH GmbH.
Research Groups and Themes
- Bristol BioDesign Institute
- Max Planck Bristol