The Golgi stacking protein GRASP55 is targeted by the natural compound prodigiosin

Autor: Lena Berning, Thomas Lenz, Ann Kathrin Bergmann, Gereon Poschmann, Hannah U. C. Brass, David Schlütermann, Annabelle Friedrich, María José Mendiburo, Céline David, Seda Akgün, Jörg Pietruszka, Kai Stühler, Björn Stork
Jazyk: angličtina
Rok vydání: 2023
Předmět:
Zdroj: Cell Communication and Signaling, Vol 21, Iss 1, Pp 1-24 (2023)
Druh dokumentu: article
ISSN: 1478-811X
DOI: 10.1186/s12964-023-01275-1
Popis: Abstract Background The bacterial secondary metabolite prodigiosin has been shown to exert anticancer, antimalarial, antibacterial and immunomodulatory properties. With regard to cancer, it has been reported to affect cancer cells but not non-malignant cells, rendering prodigiosin a promising lead compound for anticancer drug discovery. However, a direct protein target has not yet been experimentally identified. Methods We used mass spectrometry-based thermal proteome profiling in order to identify target proteins of prodigiosin. For target validation, we employed a genetic knockout approach and electron microscopy. Results We identified the Golgi stacking protein GRASP55 as target protein of prodigiosin. We show that prodigiosin treatment severely affects Golgi morphology and functionality, and that prodigiosin-dependent cytotoxicity is partially reduced in GRASP55 knockout cells. We also found that prodigiosin treatment results in decreased cathepsin activity and overall blocks autophagic flux, whereas co-localization of the autophagosomal marker LC3 and the lysosomal marker LAMP1 is clearly promoted. Finally, we observed that autophagosomes accumulate at GRASP55-positive structures, pointing towards an involvement of an altered Golgi function in the autophagy-inhibitory effect of this natural compound. Conclusion Taken together, we propose that prodigiosin affects autophagy and Golgi apparatus integrity in an interlinked mode of action involving the regulation of organelle alkalization and the Golgi stacking protein GRASP55. Video Abstract
Databáze: Directory of Open Access Journals
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