Journal Article

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

Hornberger, Annika, Neumann, Manuela, Buravlova, Oleksandra, Schymkowitz, Joost, Rousseau, Frederic, Paulsen, Lydia, Vorberg, Ina M., Konstantoulea, Katerina, Heumüller, Stefanie-Elisabeth, Denner, Philip, Müller, Stephan A., Lichtenthaler, Stefan F., Hossinger, André, Liu, Shu

2021

Overview

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. Pathologic protein aggregates associated with neurodegenerative diseases have the ability to transmit to unaffected cells via extracellular vesicles or direct cell-to-cell contact. Here, Liu et al. show that viral glycoproteins can contribute to intercellular proteopathic seed transmission via both routes.

• Publisher: Nature Publishing Group UK,Nature Publishing Group,Nature Portfolio
• Subject: 14/19 / 14/28 / 14/35 / 42/109 / 42/44 / 42/56 / 42/70 / 42/89 / 631/378/1689/364 / 631/80/304 / 82/1 / 82/83 / Adult / Aged / Aggregates / Angiotensin-Converting Enzyme 2 - metabolism / Brain - pathology / Cargo / Case-Control Studies / Cell Line / Endocytosis / Exchanging / Extracellular vesicles / Extracellular Vesicles - metabolism / Female / Glycoproteins / Humanities and Social Sciences / Humans / Intravital Microscopy / Ligands / Male / Membrane Glycoproteins - metabolism / Middle Aged / multidisciplinary / Neurodegenerative diseases / Prion protein / Prions / Prions - metabolism / Protein Aggregation, Pathological - pathology / Protein Aggregation, Pathological - virology / Protein Folding / Proteins / Receptors / Science / Science (multidisciplinary) / Seeds / Severe acute respiratory syndrome coronavirus 2 / Spike Glycoprotein, Coronavirus - metabolism / Spreading / Stomatitis / Tau protein / tau Proteins - metabolism / Vesicles / Viral diseases / Viral Envelope Proteins - metabolism