Extensive location bias of the GPCR-dependent translatome via site-selective activation of mTOR
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ABSTRACT:
PROVIDER: PRJNA1120398 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR29294565_1.fastq.gz | Fastqsanger.gz | |||
| SRR29294565_2.fastq.gz | Fastqsanger.gz | |||
| SRR29294566_1.fastq.gz | Fastqsanger.gz | |||
| SRR29294566_2.fastq.gz | Fastqsanger.gz | |||
| SRR29294567_1.fastq.gz | Fastqsanger.gz |
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Project description:G protein-coupled receptors (GPCRs) modulate various physiological functions by re-wiring cellular gene expression in response to extracellular signals. Control of gene expression by GPCRs has been studied almost exclusively at the transcriptional level, neglecting an extensive amount of regulation that takes place translationally. Hence, little is known about the nature and mechanisms of gene-specific post-transcriptional regulation downstream of receptor activation. Here, we apply an unbiased multiomics approach to delineate an extensive translational regulatory program initiated by the prototypical beta2-adrenergic receptor (β2-AR) and provide mechanistic insights into how these processes are orchestrated. Using ribosome profiling (Ribo-seq), we identify nearly 120 novel gene targets of adrenergic receptor activity for which expression is exclusively regulated at the level of translation. We next show that all translational changes are induced selectively by endosomal β2-ARs and report that this proceeds through activation of the mammalian target of rapamycin (mTOR) pathway. Specifically, within the set of translational GPCR targets we discover significant enrichment of genes with 5' terminal oligopyrimidine (TOP) motifs, a gene class classically known to be translationally regulated by mTOR. We then demonstrate that endosomal β2-ARs are required for mTOR activation and subsequent mTOR-dependent TOP mRNA translation. This site-selective crosstalk between the pathways is observed in multiple cell models with native β2-ARs, across a range of endogenous and synthetic adrenergic agonists, and for other GPCRs with intracellular activity. Together, this comprehensive analysis of drug-induced translational regulation establishes a critical role for location-biased GPCR signaling in fine-tuning the cellular protein landscape.
2025-01-19 | GSE269144 | GEO
Project description:Subcellular location defines GPCR signal transduction
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Project description:The involvement of G-Protein-Coupled Receptors’ (GPCR) location bias in diverse cellular functions and their misregulation in pathology is an underexplored territory. HCAR1, a GPCR for lactate is linked to cancer progression, mainly due to Warburg effect, but its mechanism of action remains elusive. Here, we show HCAR1 has a nuclear localization, capable of signaling intranuclearly to induce nuclear-ERK and AKT phosphorylation concomitant with higher cancer cell proliferation and survival. We determine its nuclear interactome, proving its involvement in protein-translation and DNA-damage repair. Nuclear HCAR1 (N-HCAR1) directly interacts with chromatin/DNA promoting expression of genes involved in cellular migration. Notably, we show N-HCAR1 particularly regulates a broader transcriptomic signature than its plasma membrane counterpart, emphasizing on the facts that functional output of N-HCAR1 is larger than plasma membrane localized HCAR1. Our study presents several unprecedented processes by which a GPCR through location-biased activity regulate various cellular functions and how cancer cells exploit these.
2025-01-22 | PXD035882 | Pride
Project description:The involvement of G-Protein-Coupled Receptors’ (GPCR) location bias in diverse cellular functions and their misregulation in pathology is an underexplored territory. HCAR1, a GPCR for lactate is linked to cancer progression, mainly due to Warburg effect, but its mechanism of action remains elusive. Here, we show HCAR1 has a nuclear localization, capable of signaling intranuclearly to induce nuclear-ERK and AKT phosphorylation concomitant with higher cancer cell proliferation and survival. We determine its nuclear interactome, proving its involvement in protein-translation and DNA-damage repair. Nuclear HCAR1 (N-HCAR1) directly interacts with chromatin/DNA promoting expression of genes involved in cellular migration. Notably, we show N-HCAR1 particularly regulates a broader transcriptomic signature than its PM counterpart, emphasizing on the facts that functional output of N-HCAR1 is larger than PM localized HCAR1. Our study presents several unprecedented processes by which a GPCR through location-biased activity regulate various cellular functions and how cancer cells exploit these.
2023-11-15 | GSE210455 | GEO
Project description:The involvement of G-Protein-Coupled Receptors’ (GPCR) location bias in diverse cellular functions and their misregulation in pathology is an underexplored territory. HCAR1, a GPCR for lactate is linked to cancer progression, mainly due to Warburg effect, but its mechanism of action remains elusive. Here, we show HCAR1 has a nuclear localization, capable of signaling intranuclearly to induce nuclear-ERK and AKT phosphorylation concomitant with higher cancer cell proliferation and survival. We determine its nuclear interactome, proving its involvement in protein-translation and DNA-damage repair. Nuclear HCAR1 (N-HCAR1) directly interacts with chromatin/DNA promoting expression of genes involved in cellular migration. Notably, we show N-HCAR1 particularly regulates a broader transcriptomic signature than its PM counterpart, emphasizing on the facts that functional output of N-HCAR1 is larger than PM localized HCAR1. Our study presents several unprecedented processes by which a GPCR through location-biased activity regulate various cellular functions and how cancer cells exploit these.
2023-11-15 | GSE210469 | GEO
Project description:Nuclear Location Bias of HCAR1 Drives Cancer Malignancy through Numerous Routes
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Project description:Nuclear Location Bias of HCAR1 Drives Cancer Malignancy through Numerous Routes [RNA-seq]
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Project description:Nuclear Location Bias of HCAR1 Drives Cancer Malignancy through Numerous Routes [ChIP-seq]
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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
Project description:G-protein-coupled receptors (GPCRs) are increasingly recognized to operate from intracellular membranes as well as the plasma membrane. The ?2-adrenergic GPCR can activate Gs-linked cyclic AMP (Gs-cAMP) signaling from endosomes. We show here that the homologous human ?1-adrenergic receptor initiates an internal Gs-cAMP signal from the Golgi apparatus. By developing a chemical method to acutely squelch G-protein coupling at defined membrane locations, we demonstrate that Golgi activation contributes significantly to the overall cellular cAMP response. Golgi signaling utilizes a preexisting receptor pool rather than receptors delivered from the cell surface, requiring separate access of extracellular ligands. Epinephrine, a hydrophilic endogenous ligand, accesses the Golgi-localized receptor pool by facilitated transport requiring the organic cation transporter 3 (OCT3), whereas drugs can access the Golgi pool by passive diffusion according to hydrophobicity. We demonstrate marked differences, among both agonist and antagonist drugs, in Golgi-localized receptor access and show that ?-blocker drugs currently used in the clinic differ markedly in ability to antagonize the Golgi signal. We propose 'location bias' as a new principle for achieving functional selectivity of GPCR-directed drug action.
| S-EPMC5733145 | biostudies-literature