The inhibitor Endosidin 4 targets SEC7 domain-type ARF GTPase exchange factors and interferes with sub cellular trafficking in eukaryotes Journal Article


Author(s): Kania, Urszula; Nodzyński, Tomasz; Lu, Qing; Hicks Glenn R; Nerinckx Wim; Mishev, Kiril; Peurois Francois; Cherfils Jacqueline; De Rycke Riet Maria; Grones, Peter; Robert, Stéphanie; Russinova, Eugenia; Friml, Jiří
Article Title: The inhibitor Endosidin 4 targets SEC7 domain-type ARF GTPase exchange factors and interferes with sub cellular trafficking in eukaryotes
Affiliation IST Austria
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 (PIN) 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 (Sacharomyces 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.
Journal Title: The Plant Cell
ISSN: 1532-298X
Publisher: NLM  
Publication Place: United States
Date Published: 2018-07-01
Start Page: 2553
End Page: 2572
Copyright Statement: CC BY 4.0
Sponsor: European Research Council (ERC) 282300 and 742985, Seventh Framework Programme (EC Seventh Framework Programme) LM2015062
DOI: 10.1105/tpc.18.00127
Notes: The research leading to these results was funded by the European Research Council under the European Union’s 7th Framework Program (FP7/2007-2013)/ERC grant agreement numbers 282300 and 742985 and the Czech Science Foundation GAČR (GA18-26981S; J.F.); Ministry of Education, Youth, and Sports/MEYS of the Czech Republic under the Project CEITEC 2020 (LQ1601; T.N.); the China Science Council for a predoctoral fellowship (Q.L.); a joint research project within the framework of cooperation between the Research Foundation-Flanders and the Bulgarian Academy of Sciences (VS.025.13N; K.M. and E.R.); Vetenskapsrådet and Vinnova (Verket för Innovationssystem; S.R.), Knut och Alice Wallenbergs Stiftelse via “Shapesystem” Grant 2012.0050 (S.R.), Kempe stiftelserna (P.G.), Tryggers CTS410 (P.G.).
Open access: yes (OA journal)