Image‐Based Morphological Profiling Identifies a Lysosomotropic, Iron‐Sequestering Autophagy Inhibitor. Issue 14 (24th January 2020)

• Record Type: Journal Article
• Authors: Laraia, Luca; Garivet, Guillaume; Foley, Daniel J.; Kaiser, Nadine; Müller, Sebastian; Zinken, Sarah; Pinkert, Thomas; Wilke, Julian; Corkery, Dale; Pahl, Axel; Sievers, Sonja; Janning, Petra; Arenz, Christoph; Wu, Yaowen; Rodriguez, Raphaël; Waldmann, Herbert
• Is Part Of: Angewandte Chemie international edition. Volume 59:Issue 14(2020)
• Page Start: 5721
• Page End: 5729
• Publication Date: 2020-01-24
• Subjects: autophagy -- cell painting -- lysosome -- proteomics -- target identification; Chemistry -- Periodicals; 540
• DOI: 10.1002/anie.201913712
• Languages: English
• ISSNs: 1433-7851

Abstract

Abstract: Chemical proteomics is widely applied in small‐molecule target identification. However, in general it does not identify non‐protein small‐molecule targets, and thus, alternative methods for target identification are in high demand. We report the discovery of the autophagy inhibitor autoquin and the identification of its molecular mode of action using image‐based morphological profiling in the cell painting assay. A compound‐induced fingerprint representing changes in 579 cellular parameters revealed that autoquin accumulates in lysosomes and inhibits their fusion with autophagosomes. In addition, autoquin sequesters Fe 2+ in lysosomes, resulting in an increase of lysosomal reactive oxygen species and ultimately cell death. Such a mechanism of action would have been challenging to unravel by current methods. This work demonstrates the potential of the cell painting assay to deconvolute modes of action of small molecules, warranting wider application in chemical biology. Abstract : I heard you paint cells : Morphological profiling using the "cell painting" assay revealed that autoquin impairs lysosomal integrity, iron homeostasis, and autophagy.