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 (Saccharomyces 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.

Center for Plant Cell Biology and Department of Botany and Plant Sciences University of California Riverside California 92521

Department of Plant Biotechnology and Bioinformatics Ghent University and Center for Plant Systems Biology VIB 9052 Ghent Belgium

Institute of Plant Physiology and Genetics Bulgarian Academy of Sciences 1113 Sofia Bulgaria

Institute of Science and Technology Austria 3400 Klosterneuburg Austria

Laboratoire de Biologie et Pharmacologie Appliquée CNRS Ecole Normale Supérieure Paris Saclay 94235 Cachan France

Laboratory for Protein Biochemistry and Biomolecular Engineering Department of Biochemistry and Microbiology Ghent University 9000 Ghent Belgium

Mendel Centre for Plant Genomics and Proteomics Central European Institute of Technology Masaryk University CZ 625 00 Brno Czech Republic

Umeå Plant Science Centre Department of Forest Genetics and Plant Physiology Swedish University of Agricultural Sciences 90183 Umeå Sweden

VIB BioImaging Core 9052Ghent Belgium

VIB UGent Center for Medical Biotechnology 9052 Ghent Zwijnaarde Belgium

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