期刊
ADVANCED SCIENCE
卷 9, 期 13, 页码 -出版社
WILEY
DOI: 10.1002/advs.202200201
关键词
bottom-up synthetic biology; CD95; ectosomes; Fas; FasL; immunological synapse; receptor multimerization
资金
- Federal Ministry of Education and Research of Germany [13XP5073A]
- MaxSynBio Consortium - Federal Ministry of Education and Research of Germany
- MaxSynBio Consortium - Max Planck Society
- German Science Foundation [SFB 1129]
- Deutsche Forschungsgemeinschaft (DFG, German Research Foundation) under Germany's Excellence Strategy via the Excellence Cluster 3D Matter Made [EXC-2082/1 - 390761711]
- Volkswagen Stiftung
- Heidelberg Bioscience International Graduate School
- Max Planck School Matter to Life
- Joachim Herz Foundation
Extracellular vesicles (EVs) play a fundamental role in the proper physiological functioning of multicellular organisms by shuttling nucleic acids and proteins between cells to regulate a plethora of cellular processes, especially immune signalling. In this study, the authors investigate vesicle-induced receptor sequestration (VIRS) as a universal mechanism that enhances the signalling potency of proteins presented on EV membranes. They propose that vesicle-triggered local clustering of membrane receptors is the principle structural mechanism underlying EV-based protein presentation.
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.
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