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Withanolide analogues disrupt a leukemic dependency on cholesterol transport by inhibiting the oxysterol-binding protein OSBP [CRISPR screen]

ABSTRACT: Metabolic alterations in cancers precipitate in associated dependencies that can be therapeutically exploited. To meet this goal, natural product inspired small molecules can provide a resource of underexplored chemotypes. Here, we identify W7, a synthetic withanolide analog with pronounced anti-leukemic properties via orthogonal chemical screening. Through multi-omics profiling and genome-scale CRISPR/Cas9 screens, we identify that W7 disrupts Golgi homeostasis via a mechanism that requires active PI4P signaling at the ER-Golgi membrane interface. Thermal proteome profiling and genetic validation studies reveal the oxysterol-binding protein OSBP as the direct and phenotypically relevant target of W7. Collectively, these data reaffirm sterol transport as a therapeutically actionable dependency in leukemia and motivate ensuing translational investigation via the probe-like compound W7.

ORGANISM(S): Homo sapiens

PROVIDER: GSE226848 | GEO | 2023/03/15

REPOSITORIES: GEO

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Withanolide analogues disrupt a leukemic dependency on cholesterol transport by inhibiting the oxysterol-binding protein OSBP [RNA-Seq]

Project description:Metabolic alterations in cancers precipitate in associated dependencies that can be therapeutically exploited. To meet this goal, natural product inspired small molecules can provide a resource of underexplored chemotypes. Here, we identify W7, a synthetic withanolide analog with pronounced anti-leukemic properties via orthogonal chemical screening. Through multi-omics profiling and genome-scale CRISPR/Cas9 screens, we identify that W7 disrupts Golgi homeostasis via a mechanism that requires active PI4P signaling at the ER-Golgi membrane interface. Thermal proteome profiling and genetic validation studies reveal the oxysterol-binding protein OSBP as the direct and phenotypically relevant target of W7. Collectively, these data reaffirm sterol transport as a therapeutically actionable dependency in leukemia and motivate ensuing translational investigation via the probe-like compound W7.

2023-03-15 | GSE226847 | GEO

Orpinolide disrupts a leukemic dependency on cholesterol transport by inhibiting the oxysterol-binding protein OSBP

Project description:Metabolic alterations in cancer precipitate in associated dependencies that can be therapeutically exploited. To meet this goal, natural product inspired small molecules can provide a resource of invaluable chemotypes. Here, we identify orpinolide, a synthetic withanolide analog with pronounced anti-leukemic properties via orthogonal chemical screening. Through multi-omics profiling and genome-scale CRISPR/Cas9 screens, we identify that orpinolide disrupts Golgi homeostasis via a mechanism that requires active phosphatidylinositol 4-phosphate (PI4P) signaling at the endoplasmic reticulum (ER)-Golgi membrane interface. Thermal proteome profiling and genetic validation studies reveal the oxysterol-binding protein OSBP as the direct and phenotypically relevant target of orpinolide. Collectively, these data reaffirm sterol transport as a therapeutically actionable dependency in leukemia and motivate ensuing translational investigation via the probe-like compound orpinolide.

2023-03-15 | GSE226849 | GEO

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Project description:Abnormal distribution of cellular cholesterol is associated with numerous diseases, including cardiovascular and neurodegenerative diseases. Regulated transport of cholesterol is critical for maintaining its proper distribution in the cell, yet the underlying mechanisms remain unclear. Here, we show that lipid transfer proteins, namely ORP9, OSBP, and GRAMD1s/Asters (GRAMD1a/GRAMD1b/GRAMD1c), control non-vesicular cholesterol transport at points of contact between the ER and the trans-Golgi network (TGN), thereby maintaining cellular cholesterol distribution. ORP9 localizes to the TGN via interaction between its tandem α-helices and ORP10/ORP11. ORP9 extracts PI4P from the TGN to prevent its overaccumulation and suppresses OSBP-mediated PI4P-driven cholesterol transport to the Golgi. By contrast, GRAMD1s transport excess cholesterol from the Golgi to the ER, thereby preventing its build-up. Cells lacking ORP9 exhibit accumulation of cholesterol at the Golgi, which is further enhanced by additional depletion of GRAMD1s with major accumulation in the plasma membrane. This is accompanied by chronic activation of the SREBP-2 signalling pathway. Our findings reveal the importance of regulated lipid transport at ER-Golgi contacts for maintaining cellular cholesterol distribution and homeostasis.

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Identification of genes essential for the cell death induced by OSW-1 using the Genome-wide CRISPR-Cas9 knockout (GeCKO) screening

Project description:The Golgi stress response is an important cytoprotective system that enhances Golgi function in response to cellular demand, while cells damaged by prolonged Golgi stress undergo cell death. OSW-1, a natural compound with anticancer activity, potently inhibits OSBP that transports cholesterol and phosphatidylinositol-4-phosphate (PI4P) at contact sites between the endoplasmic reticulum and the Golgi apparatus. Previously, we reported that OSW-1 induces the Golgi stress response, resulting in Golgi stress- induced transcription and cell death. However, the underlying molecular mechanism has been unknown. To reveal the mechanism of a novel pathway of the Golgi stress response regulating transcriptional induction and cell death (the PI4P pathway), we performed a genome-wide knockout screen and found that transcriptional induction as well as cell death induced by OSW-1 was repressed by the loss of regulators of PI4P synthesis, such as PITPNB and PI4KB. Our data indicate that OSW-1 induces Golgi stress-dependent transcriptional induction and cell death through dysregulation of the PI4P metabolism in the Golgi.

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Identification of human gene expression induced by OSW-1 treatment

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Lipid exchange at ER-trans Golgi contact sites governs polarized cargo sorting

Project description:Oxysterol Binding Protein (OSBP) extracts cholesterol from the ER to deliver it to the TGN via the counter exchange and subsequent hydrolysis of the phosphoinositide PI(4)P. Here, we show that this pathway is essential in polarized epithelial cells where it contributes not only to the proper subcellular distribution of cholesterol, but also to the trans-Golgi sorting and trafficking of numerous plasma membrane cargo proteins with apical or basolateral localization. Reducing the expression of OSBP, blocking its activity or inhibiting a PI4Kinase that fuels OSBP with PI(4)P abolishes the epithelial phenotype. Waves of cargo enrichment in the TGN in phase with OSBP and PI(4)P dynamics suggest that OSBP promotes the formation of lipid gradients along the TGN, which help cargo sorting. During their transient passage through the trans-Golgi, polarized plasma membrane proteins get close to OSBP, but fail to be sorted when OSBP is silenced. Thus, OSBP lipid exchange activity is decisive for polarized cargo sorting and distribution in epithelial cells.

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Global effects of pharmacologic inhibition of OSBP in human umbilical vein endothelial cells

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Priming by IKKβ recruits NLRP3 to the trans-Golgi network to enable NEK7-independent inflammasome activation

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Selective inhibition of OSBP blocks retrograde trafficking by inducing partial Golgi degradation

Project description:The dataset contains mass spectrometric raw data from two series of TMT-based expression proteomics aimed at studying the selectivity profile of oxybipin-2 and proteins affected under the treatment of OSBP inhibitors. The dataset comprises the raw data for the ITDRF of oxybipin-2 at 4 different concentrations (TMTpro, processed by Proteome Discoverer), 4 OSBP inhibitors such as C3 and OSW-1 (TMTpro, processed by Proteome Discoverer) measured on both tested-compounds and DMSO (vehicle), each collected in 30 fractions. The experiments were performed in three independent replicates for each compound (R1-R3).

2023-10-12 | MSV000093086 | MassIVE

Selective inhibition of OSBP blocks retrograde trafficking by inducing partial Golgi degradation

Project description:The dataset contains mass spectrometric raw data from two series of TMT-based expression proteomics aimed at identifying new sterol binding proteins by targeted degradation and proteins affected under the treatment of OSBP inhibitors and manganese. The dataset comprises the raw data for the 4 different sterol-containing chemical chimeras (C1-C4, TMT11plex, processed by Maxquant), 3 OSBP inhibitors namely oxybipin-1/2, C3_Me and manganese (TMTpro, processed by Proteome Discoverer) measured on both tested-compounds and DMSO (vehicle), each collected in 30 fractions. The experiments were performed in three independent replicates for each compound (R1-R3).

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