of 19
Lee
et al
. eLife 2023;12:e82874. DOI: https://doi.org/10.7554/eLife.82874
1 of 19
An extracellular vesicle targeting ligand
that binds to Arc proteins and facilitates
Arc transport in vivo
Peter H Lee*, Michael Anaya, Mark S Ladinsky, Justin M Reitsma
, Kai Zinn*
Division of Biology and Biological Engineering, California Institute of Technology,
Pasadena, United States
Abstract
Communication between distant cells can be mediated by extracellular vesicles (EVs)
that deliver proteins and RNAs to recipient cells. Little is known about how EVs are targeted to
specific cell types. Here, we identify the
Drosophila
cell-
surface protein Stranded at second (Sas) as
a targeting ligand for EVs. Full-
length Sas is present in EV preparations from transfected
Drosophila
Schneider 2 (S2) cells. Sas is a binding partner for the Ptp10D receptor tyrosine phosphatase, and
Sas-
bearing EVs preferentially target to cells expressing Ptp10D. We used co-
immunoprecipitation
and peptide binding to show that the cytoplasmic domain (ICD) of Sas binds to dArc1 and mamma-
lian Arc. dArc1 and Arc are related to retrotransposon Gag proteins. They form virus-
like capsids
which encapsulate
Arc
and other mRNAs and are transported between cells via EVs. The Sas ICD
contains a motif required for dArc1 binding that is shared by the mammalian and
Drosophila
amyloid
precursor protein (APP) orthologs, and the APP ICD also binds to mammalian Arc. Sas facilitates
delivery of dArc1 capsids bearing
dArc1
mRNA into distant Ptp10D-
expressing recipient cells in
vivo.
Editor's evaluation
The manuscript addresses how extracellular vesicles (EV) are targeted to their recipient cells once
they are produced and released. The study shows that a transmembrane protein Sas gets incorpo-
rated into EVs, and this protein binds to its receptor Ptp10D on target cells, thus targeting the EVs.
The expression of dARC1 in the EV-
producing cells leads to the increased expression of the protein
dARC1 protein and mRNAs in the recipient cells.
Introduction
Extracellular vesicles (EVs) are mediators of cell-
cell communication that transport specific protein and
RNA cargoes. They are a heterogeneous collection of vesicular structures that are exported from cells
by a variety of mechanisms. Exosomes are 30–150 nm in diameter and are released into cell superna-
tants
via
fusion of multivesicular bodies (MVBs) with the plasma membrane. Exosomes and other EVs
carry specific proteins and RNAs, and EVs derived from different cell types contain different cargoes.
EV cargoes are biomarkers for specific diseases. Because EVs can encapsulate RNAs and protect them
from degradation, and then deliver those RNAs to recipient cells, they represent a promising new type
of therapeutic agent (
O’Brien et al., 2020
;
Teng and Fussenegger, 2020
).
Little is known about mechanisms involved in EV targeting to specific cell types. EVs are internal-
ized into cells after receptor binding using a variety of endocytic mechanisms, resulting in the delivery
of their cargoes into the recipient cells. They can also directly activate intracellular signaling without
endocytosis by interacting with cell surface receptors. In this paper, we identify Stranded at second
RESEARCH ARTICLE
*For correspondence:
hlee@caltech.edu (PHL);
zinnk@caltech.edu (KZ)
Present address:
AbbVie,
Illinois, United States
Competing interest:
See page
17
Funding:
See page 17
Received:
21 August 2022
Preprinted:
08 September 2022
Accepted:
15 June 2023
Published:
16 June 2023
Reviewing Editor:
K
VijayRaghavan, National
Centre for Biological Sciences,
Tata Institute of Fundamental
Research, India
Copyright Lee
et al
. This
article is distributed under the
terms of the Creative Commons
Attribution License, which
permits unrestricted use and
redistribution provided that the
original author and source are
credited.