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@ARTICLE{Corsi:277552,
author = {Corsi, Jessica and Semnani, Pouriya Sharbatian and Peroni,
Daniele and Belli, Romina and Morelli, Alessia and
Lassandro, Michelangelo and Sidarovich, Viktoryia and Adami,
Valentina and Valentini, Chiara and Cavallerio, Paolo and
Grosskreutz, Julian and Fabbiano, Fabrizio and Grossmann,
Dajana and Hermann, Andreas and Tell, Gianluca and Basso,
Manuela and D'Agostino, Vito G},
title = {{S}mall molecule inhibitors of hn{RNPA}2{B}1-{RNA}
interactions reveal a predictable sorting of {RNA} subsets
into extracellular vesicles.},
journal = {Nucleic acids research},
volume = {53},
number = {5},
issn = {0305-1048},
address = {Oxford},
publisher = {Oxford Univ. Press},
reportid = {DZNE-2025-00441},
pages = {gkaf176},
year = {2025},
abstract = {Extracellular vesicles (EVs) are cell-secreted membranous
particles contributing to intercellular communication.
Coding and noncoding RNAs can be detected as EV cargo, and
RNA-binding proteins (RBPs), such as hnRNPA2B1, have been
circumstantially implicated in EV-RNA sorting mechanisms.
However, the contribution of competitive RBP-RNA
interactions responsible for RNA-sorting outcomes is still
unclear, especially for predicting the EV-RNA content. We
designed a reverse proteomic analysis exploiting the EV-RNA
to identify intracellular protein binders in vitro. Using
cells expressing a recombinant hnRNPA2B1 to normalize
competitive interactions, we prioritized a network of
heterogeneous nuclear ribonucleoproteins and purine-rich RNA
sequences subsequently validated in secreted EV-RNA through
short fluorescent RNA oligos. Then, we designed a
GGGAG-enriched RNA probe that efficiently interacted with a
full-length human hnRNPA2B1 protein. We exploited the
interaction to conduct a pharmacological screening and
identify inhibitors of the protein-RNA binding. Small
molecules were orthogonally validated through biochemical
and cell-based approaches. Selected drugs remarkably
impacted secreted EV-RNAs and reduced an RNA-dependent,
EV-mediated paracrine activation of NF-kB in recipient
cells. These results demonstrate the relevance of
post-transcriptional mechanisms for EV-RNA sorting and the
possibility of predicting the EV-RNA quality for developing
innovative strategies targeting discrete paracrine
functions.},
keywords = {Humans / Extracellular Vesicles: metabolism /
Heterogeneous-Nuclear Ribonucleoprotein Group A-B:
metabolism / Heterogeneous-Nuclear Ribonucleoprotein Group
A-B: genetics / RNA: metabolism / RNA: genetics / Protein
Binding / Proteomics: methods / HEK293 Cells / NF-kappa B:
metabolism / Small Molecule Libraries: pharmacology /
Heterogeneous-Nuclear Ribonucleoprotein Group A-B (NLM
Chemicals) / RNA (NLM Chemicals) / hnRNP A2 (NLM Chemicals)
/ NF-kappa B (NLM Chemicals) / Small Molecule Libraries (NLM
Chemicals)},
cin = {AG Hermann},
ddc = {570},
cid = {I:(DE-2719)1511100},
pnm = {353 - Clinical and Health Care Research (POF4-353)},
pid = {G:(DE-HGF)POF4-353},
typ = {PUB:(DE-HGF)16},
pubmed = {pmid:40103230},
doi = {10.1093/nar/gkaf176},
url = {https://pub.dzne.de/record/277552},
}