Clusters of bioactive compounds target dynamic endomembrane networks in vivo
Drakakaki, Georgia; Robert, Stephanie; Szatmari, Anna-Maria; Brown, Michelle Q.; Nagawa, Shingo; Van Damme, Daniel; Leonard, Marilyn; Yang, Zhenbiao; Girke, Thomas; Schmid, Sandra L.; Russinova, Eugenia; Friml, Jiri; Raikhel, Natasha V.; Hicks, Glenn R.
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.
chemical genomics; high content screen; endosidin; endosome
Proceedings of the National Academy of Sciences of the United States of America
2011, Volym: 108, nummer: 43, sidor: 17850-17855
Utgivare: NATL ACAD SCIENCES
Biochemistry and Molecular Biology
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