Highly efficient intercellular spreading of protein misfolding mediated by viral ligand-receptor interactions.

Abstract

Protein aggregates associated with neurodegenerative diseases have the ability to transmit to unaffected cells, thereby templating their own aberrant conformation onto soluble homotypic proteins. Proteopathic seeds can be released into the extracellular space, secreted in association with extracellular vesicles (EV) or exchanged by direct cell-to-cell contact. The extent to which each of these pathways contribute to the prion-like spreading of protein misfolding is unclear. Exchange of cellular cargo by both direct cell contact or via EV depends on receptor-ligand interactions. We hypothesized that enabling these interactions through viral ligands enhances intercellular proteopathic seed transmission. Using different cellular models propagating prions or pathogenic Tau aggregates, we demonstrate that vesicular stomatitis virus glycoprotein and SARS-CoV-2 spike S increase aggregate induction by cell contact or ligand-decorated EV. Thus, receptor-ligand interactions are important determinants of intercellular aggregate dissemination. Our data raise the possibility that viral infections contribute to proteopathic seed spreading by facilitating intercellular cargo transfer.

• Authors: Shu Liu, André Hossinger, Stefanie-Elisabeth Heumüller, Annika Hornberger, Oleksandra Buravlova, Katerina Konstantoulea, Stephan A Müller, Lydia Paulsen, Frederic Rousseau, Joost Schymkowitz, Stefan F Lichtenthaler, Manuela Neumann, Philip Denner, Ina M Vorberg
• Journal: Nature communications (Nat Commun) Vol. 12 Issue 1 Pg. 5739 (10 19 2021) ISSN: 2041-1723 [Electronic] England
• PMID: 34667166 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't, Video-Audio Media)
• Copyright: © 2021. The Author(s).

Chemical References

• G protein, vesicular stomatitis virus
• Membrane Glycoproteins
• Prions
• Spike Glycoprotein, Coronavirus
• Viral Envelope Proteins
• spike protein, SARS-CoV-2
• tau Proteins
• ACE2 protein, human
• Angiotensin-Converting Enzyme 2

Topics

• Adult
• Aged
• Angiotensin-Converting Enzyme 2 (metabolism)
• Brain (pathology)
• Case-Control Studies
• Cell Line
• Endocytosis
• Extracellular Vesicles (metabolism)
• Female
• Humans
• Intravital Microscopy
• Male
• Membrane Glycoproteins (metabolism)
• Middle Aged
• Prions (metabolism)
• Protein Aggregation, Pathological (pathology, virology)
• Protein Folding
• Spike Glycoprotein, Coronavirus (metabolism)
• Viral Envelope Proteins (metabolism)
• tau Proteins (metabolism)