Effects of ATP9A on Extracellular Vesicle Release and Exosomal Lipid Composition

Abstract

Numerous biological processes are regulated by the intercellular communications arising from extracellular vesicles (EVs) released from cells. However, the mechanisms that regulate the quantity of EV discharged have yet to be understood. While it is known that ATP9A, a P4-ATPase, is involved in endosomal recycling, it is not clear whether it also contributes to the release of EVs and the makeup of exosomal lipids. This study is aimed at exploring the role of human ATP9A in the process of EV release and, further, to analyze the profiles of EV lipids regulated by ATP9A. Our results demonstrate that ATP9A is located in both the intracellular compartments and the plasma membrane. The percentage of ceramides and sphingosine was found to be significantly greater in the control cells than in the ATP9A overexpression and ATP9A knockout groups. However, EV release was greater in ATP9A knockout cells, indicating that ATP9A inhibits the release of EVs. This study revealed the effects of ATP9A on the release of EVs and the lipid composition of exosomes.

Biallelic truncation variants in ATP9A are associated with a novel autosomal recessive neurodevelopmental disorder

“…A de novo balanced translocation leading to haploinsufficiency of this gene has been also proposed as the cause of moderate ID and hypotonia 37 . Downregulation of ATP9A has been associated with a significant increase of extracellular vesicles release, in particular the exosome 15,16 . Extracellular vesicles release is an important form of intercellular communication that enables the transport of several different signaling moleculesincluding proteins and RNA -without the need of direct cell-to-cell contacts.…”

“…They are the only P4-ATPase that do not require the CDC50 β -subunit for normal function and cellular localization 14 . They show different intracellular and tissue distribution: ATP9A is found in early and recycling endosomes and at a lower level at the plasma membrane, while ATP9B is only found in the trans-Golgi network 12,[14][15][16] . Similarly, the genes encoding ATP9A and ATP9B present with overlapping but different expression patterns with ATP9A mainly expressed in the brain (Human Protein Atlas, GTEx).…”

“…Suggestive of an important role of ATP9A in intercellular communication, this P4-ATPase inhibits extracellular vesicles release 15,16 .…”

Cell-free exosome-laden scaffolds for tissue repair

“…For example, a hydrogel composed of PG and TCP impacted the microenvironment of rat bone marrowderived MSCs, leading to secretion of exosomes to induce angiogenesis. 9,10 Exosomes contain a variety of biologically active substances from their parental cells, which reflects their functions in recipient cells. According to the results of multi-omics research, the composition of exosomes includes three major types of biomolecules: nucleic acids, proteins, and lipids.…”

Transporters Beam Signals from Cell Membranes

“…ATP9A and ATP10A flip phos-phatidylcholine (PC). The increased PC on the cytosolic leaflet has been shown to be a docking site for multivesicular late endosomes (MVE) [58]. High cytosolic leaflet PC concentration has been shown to inhibit actin nucleation, cell adhesion, and cell spreading [58,80].…”