| Abstract: | The exocyst complex regulates the last steps of exocytosis, which is essential to organisms across kingdoms. In humans, its dysfunction is correlated with several significant diseases, such as diabetes and cancer progression. Investigation of the dynamic regulation of the evolutionarily conserved exocyst-related processes using mutants in genetically tractable organisms such as Arabidopsis thaliana is limited by the lethality or the severity of phenotypes. We discovered that the small molecule Endosidin2 (ES2) binds to the EXO70 (exocyst component of 70 kDa) subunit of the exocyst complex, resulting in inhibition of exocytosis and endosomal recycling in both plant and human cells and enhancement of plant vacuolar trafficking. An EXO70 protein with a C-terminal truncation results in dominant ES2 resistance, uncovering possible distinct regulatory roles for the N terminus of the protein. This study not only provides a valuable tool in studying exocytosis regulation but also offers a potentially new target for drugs aimed at addressing human disease.The EXO70 (exocyst component of 70 kDa) protein is a component of the evolutionarily conserved octameric exocyst complex that tethers post-Golgi vesicles to the plasma membrane before SNARE-mediated membrane fusion (1). As an important component of the exocyst complex that mediates exocytosis, EXO70 regulates, for example, neurite outgrowth, epithelial cell polarity establishment, cell motility, and cell morphogenesis in animal cells (2–6). In plants, EXO70 proteins participate in polarized pollen tube growth, root hair growth, deposition of cell wall material, cell plate initiation and maturation, defense, and autophagy (7–12). In humans, EXO70 mediates the trafficking of the glucose transporter Glut4 to the plasma membrane that is stimulated by insulin and involved in the development of diabetes (13). A specific isoform of human EXO70 is also involved in cancer cell invasion (13–15). Endosidin2 (ES2) was identified from a plant-based chemical screen as an inhibitor of trafficking. We demonstrate that the target of ES2 is the EXO70 subunit of the exocyst and that ES2 is active in plants and mammalian systems. Significantly, no inhibitor of the exocyst complex has been reported, yet such compounds could be important for understanding the basic mechanisms of exocyst-mediated processes, for modifying secretion in biotechnological applications, and for the development of potential new drugs with higher affinity and more potent activity to control exocyst-related diseases. |
