Inhibition of OSBP blocks retrograde trafficking by inducing partial Golgi degradation

Nianzhe He, Laura Depta, Cecilia Rossetti, Lucie Caramelle, Marko Cigler, Hogan P Bryce-Rogers, Marine Michon, Oliver Rafn Dan, Joseph Hoock, Julien Barbier, Daniel Gillet, Alison Forrester, Georg E Winter, Luca Laraia

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Résumé

Sterol-binding proteins are important regulators of lipid homeostasis and membrane integrity; however, the discovery of selective modulators can be challenging due to structural similarities in the sterol-binding domains. We report the discovery of potent and selective inhibitors of oxysterol-binding protein (OSBP), which we term oxybipins. Sterol-containing chemical chimeras aimed at identifying new sterol-binding proteins by targeted degradation, led to a significant reduction in levels of Golgi-associated proteins. The degradation occurred in lysosomes, concomitant with changes in protein glycosylation, indicating that the degradation of Golgi proteins was a downstream effect. By establishing a sterol transport protein biophysical assay panel, we discovered that the oxybipins potently inhibited OSBP, resulting in blockage of retrograde trafficking and attenuating Shiga toxin toxicity. As the oxybipins do not target other sterol transporters and only stabilized OSBP in intact cells, we advocate their use as tools to study OSBP function and therapeutic relevance.

langue originaleAnglais
journalNature Chemical Biology
Les DOIs
Etat de la publicationPublié - 21 juin 2024

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