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

Cell Communication and Signaling

Research

Ann Kathrin Bergmann¹  Hannah U. C. Brass²  Jörg Pietruszka³  María José Mendiburo⁴  Lena Berning⁴  Céline David⁴  Björn Stork⁴  Annabelle Friedrich⁴  David Schlütermann⁴  Seda Akgün⁴  Gereon Poschmann⁵  Thomas Lenz⁶  Kai Stühler⁷ 

[1] Core Facility for Electron Microscopy, Medical Faculty and University Hospital Düsseldorf, Heinrich Heine University, 40225, Düsseldorf, Germany;Institute of Bioorganic Chemistry, Heinrich Heine University Düsseldorf at Forschungszentrum Jülich and Bioeconomy Science Center (BioSC), 52426, Jülich, Germany;Institute of Bioorganic Chemistry, Heinrich Heine University Düsseldorf at Forschungszentrum Jülich and Bioeconomy Science Center (BioSC), 52426, Jülich, Germany;Institute of Bio- and Geosciences: Biotechnology (IBG-1), Forschungszentrum Jülich, 52428, Jülich, Germany;Institute of Molecular Medicine I, Medical Faculty and University Hospital Düsseldorf, Heinrich Heine University, 40225, Düsseldorf, Germany;Institute of Molecular Medicine I, Proteome Research, Medical Faculty and University Hospital Düsseldorf, Heinrich Heine University, 40225, Düsseldorf, Germany;Molecular Proteomics Laboratory, Biological Medical Research Centre, Heinrich Heine University, 40225, Düsseldorf, Germany;Molecular Proteomics Laboratory, Biological Medical Research Centre, Heinrich Heine University, 40225, Düsseldorf, Germany;Institute of Molecular Medicine I, Proteome Research, Medical Faculty and University Hospital Düsseldorf, Heinrich Heine University, 40225, Düsseldorf, Germany;

关键词: Prodigiosin;    Golgi apparatus;    Natural compound;    Autophagy;    Target identification;   

DOI  :  10.1186/s12964-023-01275-1

 received in 2023-07-12, accepted in 2023-08-13,  发布年份 2023

来源: Springer

【 摘 要 】

BackgroundThe 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.MethodsWe 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.ResultsWe 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.ConclusionTaken 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 GRASP55.8brCwiZ4E3PVMoFvaLMguTVideo Abstract

【 授权许可】

CC BY   
© BioMed Central Ltd., part of Springer Nature 2023

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