The inhibitor endosidin 4 targets sec7 domain-type arf gtpase exchange factors and interferes with subcellular trafficking in eukaryotes[open]

Urszula Kania, Tomasz Nodzyński, Qing Lu, Glenn R. Hicks, Wim Nerinckx, Kiril Mishev, François Peurois, Jacqueline Cherfils, Riet De Rycke, Peter Grones, Stéphanie Robert, Eugenia Russinova, Jiří Friml*

*Corresponding author for this work

Research output: Contribution to journalArticleAcademicpeer-review

15 Citations (Scopus)

Abstract

The trafficking of subcellular cargos in eukaryotic cells crucially depends on vesicle budding, a process mediated by ARF-GEFs (ADP-ribosylation factor guanine nucleotide exchange factors). In plants, ARF-GEFs play essential roles in endocytosis, vacuolar trafficking, recycling, secretion, and polar trafficking. Moreover, they are important for plant development, mainly through controlling the polar subcellular localization of PIN-FORMED transporters of the plant hormone auxin. Here, using a chemical genetics screen in Arabidopsis thaliana, we identified Endosidin 4 (ES4), an inhibitor of eukaryotic ARF-GEFs. ES4 acts similarly to and synergistically with the established ARF-GEF inhibitor Brefeldin A and has broad effects on intracellular trafficking, including endocytosis, exocytosis, and vacuolar targeting. Additionally, Arabidopsis and yeast (Saccha-romyces cerevisiae) mutants defective in ARF-GEF show altered sensitivity to ES4. ES4 interferes with the activation-based membrane association of the ARF1 GTPases, but not of their mutant variants that are activated independently of ARF-GEF activity. Biochemical approaches and docking simulations confirmed that ES4 specifically targets the SEC7 domain-containing ARF-GEFs. These observations collectively identify ES4 as a chemical tool enabling the study of ARF-GEF-mediated processes, including ARF-GEF-mediated plant development.
Original languageEnglish
Pages (from-to)2553-2572
Number of pages20
JournalPlant Cell
Volume30
Issue number10
DOIs
Publication statusPublished - 17 Jul 2018
Externally publishedYes

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