title: Clusters of bioactive compounds target dynamic endomembrane networks in vivo.
abstract: Endomembrane trafficking relies on the coordination of a highly complex, dynamic network of intracellular vesicles. Understanding the network will require a dissection of cargo and vesicle dynamics at the cellular level in vivo. This is also a key to establishing a link between vesicular networks and their functional roles in development. We used a high-content intracellular screen to discover small molecules targeting endomembrane trafficking in vivo in a complex eukaryote, Arabidopsis thaliana. Tens of thousands of molecules were prescreened and a selected subset was interrogated against a panel of plasma membrane (PM) and other endomembrane compartment markers to identify molecules that altered vesicle trafficking. The extensive image dataset was transformed by a flexible algorithm into a marker-by-phenotype-by-treatment time matrix and revealed groups of molecules that induced similar subcellular fingerprints (clusters). This matrix provides a platform for a systems view of trafficking. Molecules from distinct clusters presented avenues and enabled an entry point to dissect recycling at the PM, vacuolar sorting, and cell-plate maturation. Bioactivity in human cells indicated the value of the approach to identifying small molecules that are active in diverse organisms for biology and drug discovery.
authors: Center for Plant Cell Biology and Department of Botany and Plant Sciences, University of California, Riverside, CA 92521, USA.
authors: Georgia
authors: G
authors: Drakakaki
authors: Stéphanie
authors: S
authors: Robert
authors: Anna-Maria
authors: AM
authors: Szatmari
authors: Michelle Q
authors: MQ
authors: Brown
authors: Shingo
authors: S
authors: Nagawa
authors: Daniel
authors: D
authors: Van Damme
authors: Marilyn
authors: M
authors: Leonard
authors: Zhenbiao
authors: Z
authors: Yang
authors: Thomas
authors: T
authors: Girke
authors: Sandra L
authors: SL
authors: Schmid
authors: Eugenia
authors: E
authors: Russinova
authors: Jiří
authors: J
authors: Friml
authors: Natasha V
authors: NV
authors: Raikhel
authors: Glenn R
authors: GR
authors: Hicks
mesh_terms: D000465:Algorithms; D017360:Arabidopsis / Q000378:metabolism*; D001692:Biological Transport / Q000502:physiology; D002462:Cell Membrane / Q000378:metabolism*; D002478:Cells, Cultured; D016000:Cluster Analysis; D005455:Fluorescent Antibody Technique; D049452:Green Fluorescent Proteins; D006367:HeLa Cells; D006801:Humans; D018613:Microscopy, Confocal; D015394:Molecular Structure; D036226:Seedlings / Q000378:metabolism; D054852:Small Molecule Libraries / Q000145:classification / Q000378:metabolism*; D059008:Time-Lapse Imaging; D014026:Nicotiana; D022161:Transport Vesicles / Q000378:metabolism*
chemical_list: D054852:Small Molecule Libraries; D049452:Green Fluorescent Proteins