Endophilin-A2 functions in membrane scission in clathrin-independent endocytosis

During endocytosis, energy is invested to narrow the necks of cargo-containing plasma membrane invaginations to radii at which the opposing segments spontaneously coalesce, thereby leading to the detachment by scission of endocytic uptake carriers1. In the clathrin pathway, dynamin uses mechanical energy from GTP hydrolysis to this effect2, 3, 4, assisted by the BIN/amphiphysin/Rvs (BAR) domain-containing protein endophilin5, 6. Clathrin-independent endocytic events are often less reliant on dynamin7, and whether in these cases BAR domain proteins such as endophilin contribute to scission has remained unexplored. Here we show, in human and other mammalian cell lines, that endophilin-A2 (endoA2) specifically and functionally associates with very early uptake structures that are induced by the bacterial Shiga and cholera toxins, which are both clathrin-independent endocytic cargoes8. In controlled in vitro systems, endoA2 reshapes membranes before scission. Furthermore, we demonstrate that endoA2, dynamin and actin contribute in parallel to the scission of Shiga-toxin-induced tubules. Our results establish a novel function of endoA2 in clathrin-independent endocytosis. They document that distinct scission factors operate in an additive manner, and predict that specificity within a given uptake process arises from defined combinations of universal modules. Our findings highlight a previously unnoticed link between membrane scaffolding by endoA2 and pulling-force-driven dynamic scission

Achieving Selective Targeting Using Engineered Nanomaterials

The development of Drug Delivery Systems (DDS) able to selectively deliver a controlled amount of a drug only to diseased cells would represent a dramatic development in nanomedicine. One of the multiple challenges still paving the way towards this goal is the elaboration of strategies that would allow targeting with extreme accuracy specific cells, as cancerous cells, among a large variety of closely related ones. In this work, we review the most recent nanotechnology applications aiming at controlling the selectivity of the interaction of delivery nanosystems with cells, with a focus on multivalent targeting. We briefly review thermodynamic models of multivalent interactions and highlight the challenges that still need to be addressed to transfer theoretical design principles into practical applications. In particular, suitable experimental systems based on multivalent models often require the control of the nanocarrier characteristics at the molecular level. Traditional delivery methods, however, fail to provide such degree of control. DNA nanotechnology is a growing field of nanoscience that has witnessed impressive developments in the past decades and has led to major advances in the fabrication of nanostructures and self-assembled systems. Relying on the possibility of controlling their molecular interactions by sequence design, nucleic acids can serve the drug delivery program by providing desired nanostructures with nearly atomic precision. In combination with the recent achievements in the research on DNA aptamers, short nucleic acid sequences isolated to interact selectively with a specific target, DNA nanotechnology is undoubtedly one of the most promising tools for the development of selective DDS.info:eu-repo/semantics/publishe