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. dArc1 and mammalian 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 Sas and APP ICDs also bind to mammalian Arc. Sas facilitates delivery of dArc1 capsids bearing dArc1 mRNA into distant Ptp10D-expressing recipient cells in vivo.
Competing Interest Statement
Justin M. Reitsma is affiliated with AbbVie. The author has no other competing interests to declare.
List of Abbreviations
- aa
- amino acid
- AD
- Alzheimer’s disease
- Ap
- apterous
- APP
- amyloid precursor protein
- Co-IP
- coimmunoprecipitation
- CSP
- cell surface protein
- ECD
- extracellular domain
- EM
- electron microscopy
- EV
- extracellular vesicle
- EVT
- 345 aa region absent from Sas PA/PC isoform
- FISH
- fluorescence in situ hybridization
- FN-III
- Fibronectin Type III
- GOF
- gain of function (overexpression)
- ICD
- cytoplasmic domain
- immuno-EM
- immuno-electron microscopy
- MVB
- multivesicular body
- NMJ
- neuromuscular junction
- NTA
- nanoparticle tracking analysis
- ORF
- open reading frame
- PTB
- phosphotyrosine binding
- Ptp10D
- Drosophila receptor tyrosine phosphatase gene located at 10D on the chromosome map
- RPTP
- receptor tyrosine phosphatase
- Sas
- Stranded at second
- SasFL
- full-length Sas (PB/PD isoform)
- Sasshort
- Sas isoform lacking EVT region (PA/PC isoform)
- SG
- salivary gland
- TM
- transmembrane
- UAS
- upstream activation sequence
- UTR
- untranslated region
- VFWC
- von Willebrand factor C
- VNC
- ventral nerve cord