Syntenin-knock out reduces exosome turnover and viral transduction

Rudra Kashyap,Guido David,Pascale Zimmermann,Benoit Lechat,Sofie Meeussen,Joanna Fares,Antonio Luis Egea-Jimenez,Kathleen Lambaerts,Frédérique Lembo,Sebastian Kügler,Anton Roebroek,Marielle Balzano

doi:10.1038/s41598-021-81697-4

Abstract

Exosomal transfers represent an important mode of intercellular communication. Syntenin is a small scaffold protein that, when binding ALIX, can direct endocytosed syndecans and syndecan cargo to budding endosomal membranes, supporting the formation of intraluminal vesicles that compose the source of a major class of exosomes. Syntenin, however, can also support the recycling of these same components to the cell surface. Here, by studying mice and cells with syntenin-knock out, we identify syntenin as part of dedicated machinery that integrates both the production and the uptake of secreted vesicles, supporting viral/exosomal exchanges. This study significantly extends the emerging role of heparan sulfate proteoglycans and syntenin as key components for macromolecular cargo internalization into cells.

Highlights

Exosomal transfers represent an important mode of intercellular communication
In a process that depends on ARF6, but requires PIPK5 as ARF6-effector and syntenin to bind PIP2, syntenin supports the recycling of syndecans and syndecan cargo back to the cell surface, avoiding their exosomal/lysosomal destinations and potentially regulating their cell surface a bundance[36]
To study the in vivo effects of a disruption of syntenin function, we developed a mouse strain with a constitutive general syntenin-knock out (KO)

Summary

Introduction

Syntenin is a small scaffold protein that, when binding ALIX, can direct endocytosed syndecans and syndecan cargo to budding endosomal membranes, supporting the formation of intraluminal vesicles that compose the source of a major class of exosomes. When providing the genetic background for a model of tau-mediated neurodegeneration that is based on the AAV6-mediated expression of mutant P301L protein tau, compared to wild-type animals, mice with syntenin-KO were found to express recombinant human tau at much lower levels and in a more restricted area of the brain. To explore this further, we established MEFs from these animals. This study significantly extends the emerging role of syntenin and HSPGs as key components for the exchange of macromolecular cargo between cells

Methods

Results

Conclusion