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Subcellular location defines GPCR signal transduction

ABSTRACT: G protein-coupled receptors in intracellular organelles can be activated in response to membrane permeant ligands, which contributes to the diversity and specificity of agonist action. The opioid receptors (ORs) provide a striking example, where small molecule opioid drugs activate ORs in the Golgi apparatus within seconds of drug addition. To date, our knowledge on the signaling of intracellular GPCRs remains incomplete and it is unknown if the downstream events triggered by ORs in plasma membrane and Golgi apparatus differ. To address this gap, we analyzed OR-mediated phosphorylation changes in cells treated with SNC80 (signaling control) or ICI-SNC80 (Golgi-restricted signaling) for 5 min or 25 min. We show that OR activation in the plasma membrane or Golgi apparatus have strikingly different downstream effects on protein phosphorylation. The study delineates OR signal transduction with unprecedented resolution and reveals that the subcellular location defines the signaling effect promoted by opioid drugs.

INSTRUMENT(S): Orbitrap Fusion Lumos

ORGANISM(S): Homo Sapiens (human)

TISSUE(S): Embryonic Cell

SUBMITTER: Lucie Oberhauser

LAB HEAD: Miriam Stoeber

PROVIDER: PXD038921 | Pride | 2023-04-25

REPOSITORIES: Pride

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Subcellular location defines GPCR signal transduction

Project description:G protein-coupled receptors in intracellular organelles can be activated in response to membrane permeant ligands, which contributes to the diversity and specificity of agonist action. The opioid receptors (ORs) provide a striking example, where small molecule opioid drugs activate ORs in the Golgi apparatus within seconds of drug addition. To date, our knowledge on the signaling of intracellular GPCRs remains incomplete and it is unknown if the downstream events triggered by ORs in plasma membrane and Golgi apparatus differ. To address this gap, we analyzed OR-mediated gene expression changes upon treatment with impermeant peptide ligand DPDPE, permeant ligand SNC80 or ICI-SNC80 (Golgi-restricted signaling). We show that DOR activation in the Golgi does not trigger any gene transcription at these two time points as compare to plasma membrane receptors. The study delineates OR signal transduction with unprecedented resolution and reveals that the subcellular location defines the signaling effect promoted by opioid drugs.

2023-04-24 | GSE221762 | GEO

Loss of GPHR in the brain

Project description:The Golgi apparatus plays a central role in the protein glycosylation where it is required for secretory trafficking. Abnormal morphology of the Golgi apparatus has been widely observed in neurodegenerative disease. Golgi pH regulator (GPHR) is an anion channel essential for acidification of the Golgi lumen and its essential for normal morphology and function of the Golgi apparatus. To address the Golgi dysfunction in neuronal cells, we established brain-specific GPHR knockout mice (GPHRf/f;Nes).

2022-08-31 | GSE208622 | GEO

An integrated global analysis of compartmentalized HRAS signaling

Project description:Modern omics technologies allow us obtaining global information on different types of biological networks. However, integrating these different types of analyzes into a coherent framework for a comprehensive biological interpretation remains challenging. Here, we present a conceptual framework that integrates protein interaction, phosphoproteomics and transcriptomics data. Applying this method to analyze HRAS signaling from different subcellular compartments shows that spatially-defined networks contribute specific functions to HRAS signaling. Changes in HRAS protein interactions at different sites lead to different kinase activation patterns that differentially regulate gene transcription. HRAS mediated signaling is the strongest from the plasma membrane, but it regulates the largest number of genes from the endoplasmic reticulum. The integrated networks provide a topologically and functionally resolved view of HRAS signaling. They reveal new HRAS functions including the control of cell migration from the endoplasmic reticulum and p53 dependent cell survival when signaling from the Golgi apparatus.

2019-03-12 | E-MTAB-7672 | biostudies-arrayexpress

ARRB1 inhibits the progression of non-alcoholic steatohepatitis by promoting the intracellular processing of GDF15

Project description:ARRB1 is a vital regulator in the development of NASH via facilitating GDF15 translocate to Golgi apparatus and maturation. ARRB1 is a potential therapeutic target for the treatment of NASH.

2022-09-09 | GSE137113 | GEO

Chemokine receptor CXCR7 activates Aurora Kinase A and promotes neuroendocrine prostate cancer growth

Project description:CXCR7, an atypical chemokine receptor (ACKR3), is up-regulated in NEPC, and its expression is associated with molecular markers of NEPC and cell proliferation. Transcriptomic analyses revealed a major role of CXCR7 in regulating downstream genes involved in the cell cycle and mitotic spindle. Membrane-bound CXCR7 is known to recruit β-arrestin (ARRB2), and the complex internalizes into clathrin-coated vesicles where they act as a scaffold for cytoplasmic kinase assembly and substrate activation. We identify Aurora Kinase A (AURKA) as a top candidate that is binding to and activated by CXCR7-ARRB2. Immunofluorescence confocal microscopy detected high-density CXCR7, ARRB2, and AURKA in the pericentrosomal area with focal staining of ARRB2 and ARUKA at centrosomes. Mass spectrometry showed that CXCR7 interacts with many proteins associated with intracellular vesicles, microtubules, and Golgi apparatus. CXCR7-ARRB2-containing vesicles traffic along the microtubules to the perinuclear Golgi apparatus, where CXCR7-ARRB2 interacts with AURKA to promote its activation and cell growth. Finally, we showed that pharmacological inhibitors of AURKA abolish CXCR7-driven tumor growth. Our study reveals CXCR7-mediated activation of AURKA and establishes CXCR7 and its downstream kinases as critical targets for therapeutic intervention in CRPC or NEPC patients.

2023-05-14 | GSE199274 | GEO

Identification of human genes of which expression are induced by 4MU-xyloside treatment

Project description:The Golgi stress response is a homeostatic mechanism that augments the functional capacity of the Golgi apparatus when Golgi function becomes insufficient (Golgi stress). Three response pathways of the Golgi stress response have been identified in mammalian cells, the TFE3, HSP47 and CREB3 pathways, which augment the capacity of specific Golgi functions such as N-glycosylation, anti-apoptotic activity and pro-apoptotic activity, respectively. On the contrary, glycosylation of proteoglycans (PGs) is another important function of the Golgi, although the response pathway upregulating expression of glycosylation enzymes for PGs in response to Golgi stress remains unknown. Here, we found that expression of glycosylation enzymes for PGs was induced upon insufficiency of PG glycosylation capacity in the Golgi (PG-Golgi stress), and that transcriptional induction of genes encoding glycosylation enzymes for PGs was independent of the known Golgi stress response pathways and ER stress response. Promoter analyses of genes encoding these glycosylation enzymes revealed the novel enhancer element PGSE, which regulates their transcriptional induction upon PG-Golgi stress. From these observations, the response pathway we discovered is a novel Golgi stress response pathway, which we have named the PG pathway.

2018-08-01 | GSE117938 | GEO

Identification of human gene expression induced by 4MU-xyloside treatment

2018-09-14 | GSE119909 | GEO

mRNA Sequencing Reveals Altered Synaptic Vesicular Transport in Post-Mortem Cerebellum

Project description:Schizophrenia (SCZ) is a common, disabling mental illness with high heritability but complex, poorly understood genetic etiology. As the first phase of a genomic convergence analysis of SCZ, we generated 16.7 billion nucleotides of short read, shotgun sequences of cDNA from post-mortem cerebellar cortices of 14 patients and six matched controls. A rigorous analysis pipeline was developed for analysis of digital gene expression studies. Sequences aligned to approximately 33,200 transcripts in each sample, with average coverage of 450 reads per gene. Following adjustments for confounding clinical, sample and experimental sources of variation, 215 genes differed significantly in expression between cases and controls. Golgi apparatus, vesicular transport, membrane association, Zinc binding and regulation of transcription were over-represented among differentially expressed genes. Twenty three genes with altered expression and involvement in presynaptic vesicular transport, Golgi function and GABAergic neurotransmission define a unifying molecular hypothesis for dysfunction in cerebellar cortex in SCZ.

2008-11-12 | GSE12297 | GEO

Identification of human gene expression induced by OSW-1 treatment

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.

2024-02-16 | GSE255894 | GEO