Welcome to the new version of CaltechAUTHORS. Login is currently restricted to library staff. If you notice any issues, please email coda@library.caltech.edu
Published June 16, 2023 | Published + Supplemental Material
Journal Article Open

An extracellular vesicle targeting ligand that binds to Arc proteins and facilitates Arc transport in vivo


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 mammalian 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.

Additional Information

© 2023, 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. Mass spectrometry work was performed at the Caltech Proteome Exploration Laboratory. Imaging was done at the Caltech Biological Imaging facility. EM work was done at the Caltech Cryo-EM facility. We thank Violana Nesterova for figure preparation. We thank the following colleagues for reagents and Drosophila lines: Jason Shepherd (University of Utah) for pGEX-dArc and rArc constructs; Travis Thomson and Vivian Budnik (University of Massachusetts) for rabbit anti-Arc1; Douglas Cavener (Penn State) for rabbit anti-SasFL; Deborah Andrew (Johns Hopkins) for Sage-GAL4; James Skeath (Washington University) for guinea pig anti-Numb; Swati Banerjee (UTHSC, San Antonio) for rat anti-Repo, and Yuh-Nung Jan (UCSF) for UAS-Numb. We thank Simon Erlendsson, Fernando Bazan, Paul Worley, and Tino Pleiner for discussions about Arc purification and Arc and Sas structures. This work was supported by NIH RO1 grants NS28182 and NS096509 to KZ, and by Howard Hughes Medical Institute support to R Deshaies, who was JMR's faculty supervisor when he was a postdoctoral fellow at Caltech. Data availability: Key data generated or analysed during this study are included in the manuscript and supporting files. Author contributions: Peter H Lee, Conceptualization, Resources, Data curation, Formal analysis, Validation, Investigation, Visualization, Methodology, Writing - original draft, Writing - review and editing; Michael Anaya, Investigation, Methodology; Mark S Ladinsky, Investigation, Visualization, Methodology; Justin M Reitsma, Resources, Software, Investigation, Methodology; Kai Zinn, Conceptualization, Supervision, Funding acquisition, Writing - original draft, Project administration, Writing - review and editing. Competing interests: Justin M Reitsma: is affiliated with AbbVie. The author has no other competing interests to declare. The other authors declare that no competing interests exist.

Attached Files

Published - elife-82874-v2.pdf

Supplemental Material - elife-82874-mdarchecklist1-v2.docx

Supplemental Material - elife-82874-supp1-v2.xlsx


Files (8.0 MB)
Name Size Download all
418.2 kB Download
103.1 kB Download
7.5 MB Preview Download

Additional details

August 22, 2023
December 22, 2023