Global Discovery of Covalent Modulators of Ribonucleoprotein Granules

Anthony M. Ciancone, Kyung W. Seo, Miaomiao Chen, Adam L. Borne, Adam H. Libby, Dina L. Bai, Ralph E. Kleiner, Ku Lung Hsu

Research output: Contribution to journalArticlepeer-review

2 Scopus citations

Abstract

Stress granules (SGs) and processing-bodies (PBs, P-bodies) are ubiquitous and widely studied ribonucleoprotein (RNP) granules involved in cellular stress response, viral infection, and the tumor microenvironment. While proteomic and transcriptomic investigations of SGs and PBs have provided insights into molecular composition, chemical tools to probe and modulate RNP granules remain lacking. Herein, we combine an immunofluorescence (IF)-based phenotypic screen with chemoproteomics to identify sulfonyl-triazoles (SuTEx) capable of preventing or inducing SG and PB formation through liganding of tyrosine (Tyr) and lysine (Lys) sites in stressed cells. Liganded sites were enriched for RNA-binding and protein-protein interaction (PPI) domains, including several sites found in RNP granule-forming proteins. Among these, we functionally validate G3BP1 Y40, located in the NTF2 dimerization domain, as a ligandable site that can disrupt arsenite-induced SG formation in cells. In summary, we present a chemical strategy for the systematic discovery of condensate-modulating covalent small molecules.

Original languageEnglish (US)
Pages (from-to)11056-11066
Number of pages11
JournalJournal of the American Chemical Society
Volume145
Issue number20
DOIs
StatePublished - May 24 2023

All Science Journal Classification (ASJC) codes

  • General Chemistry
  • Biochemistry
  • Catalysis
  • Colloid and Surface Chemistry

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