Browse
Submit Data
Databases
API
Help

Dataset Information

0 Views

0 Connections

0 Citations

0 Reanalyses

0 Downloads

Omics score: 0

Liver RBFOX2 regulates cholesterol homeostasis via Scarb1 alternative splicing in mice

ABSTRACT: RNA alternative splicing (AS) expands the regulatory potential of eukaryotic genomes. The mechanisms regulating liver-specific AS profiles and their contribution to liver function are poorly understood. Here, we identify a key role for the splicing factor RNA-binding Fox protein-2 (RBFOX2) in maintaining cholesterol homeostasis in an obesogenic environment in the liver. Using enhanced individual-nucleotide resolution UV-crosslinking and immunoprecipitation (eiCLIP), we identify physiologically relevant targets of RBFOX2 in mouse liver, including the scavenger receptor class B type I (Scarb1). RBFOX2 function is decreased in the liver in diet-induced obesity, causing a Scarb1 isoform switch and alteration of hepatocyte lipid homeostasis. Our findings demonstrate that specific AS programmes actively maintain liver physiology, and underlie the lipotoxic effects of obesogenic diets when dysregulated. Splice-switching oligonucleotides targeting this network alleviate obesityinduced inflammation in the liver and promote an anti-atherogenic lipoprotein profile in the blood, underscoring the potential of isoform-specific RNA therapeutics for treating metabolism-associated diseases.

INSTRUMENT(S): Orbitrap Fusion

ORGANISM(S): Mus Musculus (mouse)

TISSUE(S): Liver

SUBMITTER: Miguel Prado

LAB HEAD: Miguel Prado

PROVIDER: PXD036976 | Pride | 2022-11-28

REPOSITORIES: Pride

ACCESS DATA

Json Xml

Dataset's files

Source:

			Action	DRS
	365530_out.tgz	Other
	365531_out.tgz	Other
	365532_out.tgz	Other
	365533_out.tgz	Other
	365534_out.tgz	Other

Items per page:

1 - 5 of 48

Similar Datasets

UCP1-dependent depletion of liver extracellular succinate antagonizes inflammatory pathogenesis

Project description:Non-alcoholic fatty liver disease (NAFLD) is the most prevalent liver pathology worldwide and is intimately linked with obesity and type 2 diabetes. Liver inflammation is a hallmark of NAFLD and is thought to contribute to tissue fibrosis and disease pathogenesis. Uncoupling protein 1 (UCP1) is exclusively expressed in brown and beige adipocytes and has been extensively studied for its capacity to elevate thermogenesis and reverse obesity. Here we identify an endocrine pathway regulated by UCP1 that antagonizes liver inflammation and pathology, independent of effects on obesity. We show that, without UCP1, brown and beige fat exhibit a diminished capacity to clear succinate from the circulation. Moreover, UCP1KO mice exhibit elevated extracellular succinate in liver tissue that drives inflammation through ligation of its cognate receptor succinate receptor 1 (SUCNR1) in liver-resident stellate cell and macrophage populations. Conversely, increasing brown and beige adipocyte content in mice antagonizes SUCNR1-dependent inflammatory signaling in the liver. We show that this UCP1-succinate-SUCNR1 axis is necessary to regulate liver immune cell infiltration and pathology, and systemic glucose intolerance in an obesogenic environment. As such, the therapeutic utility of brown and beige adipocytes, and UCP1, extends beyond thermogenesis and may be leveraged to antagonize NAFLD and SUCNR1-dependent liver inflammation.

2022-02-17 | PXD024717 | Pride

Phosphorylation patterns on the c-terminal tail of the angiotensin II type 1 receptor encode differential signaling pathways

Project description:Structural studies have recently shown that mechanism of selective AT1R activation by different classes of ligands is initiated by the ability of ligands to stabilize unique active conformations of the receptor. Active conformations enhance transducer coupling leading to effector mediated signaling, that has been proposed to be linked to differential phosphorylation of the c-terminal tail of the receptor. To determine how different classes of AT1R ligands effect receptor phosphorylation and activation of downstream signaling we used TMT-MS to identify the amino acid residues of the AT1R phosphorylated following treatment with the full balanced agonist Angiotensin II and a β-arrestin biased ligand, TRV023. Here we show that Ang and TRV 023 induce two distinct patterns of phosphorylation clusters a.a. residues along the entire c-tail with AngII inducing a greater magnitude than the β-arrestin biased ligand TRV 023, particularly in the proximal part of the tail. Selective mutagenesis of Ser and Thr residues, we found that of the 12 Ser/Thr residues within the c-tail, only the 4 proximal and 4 middle residues are all required for full β -arrestin functionality in response to either a balanced or β-arrestin-based ligand. Surprisingly, phosphorylation of 4 residues in the proximal c-tail is necessary for maximal G-protein activation to a full agonist. Taken together our data demonstrate that a AT1R ligands that stabilize different active confirmations of the receptor (full agonist vs. β-arrestin biased) induce distinct phosphorylation patterns on the c-tail of the receptor to evoke distinct receptor-transducer engagement and downstream receptor trafficking and signaling.

2024-07-15 | PXD032672 | Pride

USP14 inhibition enhances Parkin-independent mitophagy in iNeurons

Project description:Loss of proteostasis is well documented during physiological aging and depends on the progressive decline in the activity of two major degradative mechanisms: the ubiquitin-proteasome system (UPS) and the autophagy-lysosomal pathway. This decline in proteostasis is exacerbated in age-associated neurodegenerative diseases, such as Parkinson’s Disease (PD). In PD, patients develop an accumulation of aggregated proteins and dysfunctional mitochondria, which leads to ROS production, neuroinflammation and neurodegeneration. We recently reported that inhibition of the deubiquitinating enzyme USP14, which is known to enhance both the UPS and autophagy, increases lifespan and rescues the pathological phenotype of two Drosophila models of PD. Studies on the effects of USP14 inhibition in mammalian neurons have not yet been conducted. To close this gap, we exploited iNeurons differentiated from human embryonic stem cells (hESCs), and investigated the effect of inhibiting USP14 in these cultured neurons. Quantitative global proteomics analysis performed following genetic ablation or pharmacological inhibition of USP14 demonstrated that USP14 loss of function specifically promotes mitochondrial autophagy in iNeurons. Biochemical and imaging data also showed that USP14 inhibition enhances mitophagy. The mitophagic effect of USP14 inhibition proved to be PINK1/Parkin- independent, instead relying on expression of the mitochondrial E3 Ubiquitin Ligase MITOL/MARCH5. Notably, USP14 inhibition normalized the mitochondrial defects of Parkin KO human neurons.

2024-12-18 | PXD056511 | Pride

Alkaloids modify the poison frog proteome

Project description:Poison frogs sequester chemical defenses from their diet of leaf litter arthropods for defense against predation. Little is known about the physiological adaptations that confer this unusual bioaccumulation ability. We conducted an alkaloid-feeding experiment with the Diablito poison frog (Oophaga sylvatica) to determine how quickly alkaloids are accumulated and how toxins modify frog physiology using quantitative proteomics. Diablito frogs rapidly accumulated the alkaloid decahydroquinoline within four days, and dietary alkaloid exposure modified protein abundance in the intestines, liver, and skin. Many proteins that increased in abundance with toxin accumulation are plasma glycoproteins, including the complement system and the toxin-binding protein saxiphilin. Other protein classes that change in abundance with toxin accumulation are membrane proteins involved in small molecule transport and metabolism. Overall, this work shows poison frogs can rapidly accumulate alkaloids, which alter carrier protein abundance, initiate an immune response, and alter small molecule transport and metabolism dynamics across tissues

2021-01-25 | PXD021216 | Pride

Targetable leukemia dependency on noncanonical PI3Kγ signaling

Project description:Phosphoinositide 3-kinase gamma (PI3Kγ) is implicated as a target to repolarize tumor-associated macrophages and promote anti-tumor immune responses in solid cancers. However, cancer cell-intrinsic roles of PI3Kγ are unclear. Here, by integrating unbiased genome-wide CRISPR interference screening with functional analyses across acute leukemias, we define a selective dependency on the PI3Kγ complex in a high-risk subset that includes myeloid, lymphoid, and dendritic lineages. This dependency is characterized by innate inflammatory signaling and elevation of PIK3R5, which encodes a regulatory subunit of PI3Kγ that we find stabilizes the active enzymatic complex when overexpressed. Mechanistically, we identify PAK1 kinase as a noncanonical substrate of PI3Kγ that mediates this cell-intrinsic dependency independently of AKT. PI3Kγ inhibition dephosphorylates PAK1, activates a transcriptional network of NFκB-related tumor suppressor genes, and impairs mitochondrial oxidative phosphorylation. We find that treatment with the selective PI3Kγ inhibitor eganelisib is effective in leukemias with activated PIK3R5, either at baseline or by exogenous inflammatory stimulation. Notably, the combination of eganelisib and cytarabine prolongs survival over either agent alone, even in patient-derived leukemia xenografts with low baseline PIK3R5 expression, as residual leukemia cells after cytarabine treatment have elevated G protein-coupled purinergic receptor activity and PAK1 phosphorylation. Taken together, our study reveals acute leukemia dependency on a noncanonical PI3Kγ signaling pathway amenable to near-term evaluation in patients using inhibitors already in clinical development.

2024-03-19 | PXD045702 | Pride

Mapping AT1R biased signaling using proximity-labeling and proteomics identifies diverse actions of biased agonists

Project description:Angiotensin II type 1 receptors (AT1Rs) are one of the most widely studied G protein-coupled receptors. To fully appreciate the diversity in cellular signaling profiles activated by AT1R transducer-biased ligands, we utilized peroxidase-catalyzed proximity labeling to capture proteins in close proximity to AT1Rs in response to six different ligands: Angiotensin II (full agonist), S1I8 (partial agonist), TRV055 and TRV056 (G protein-biased agonists), TRV026 and TRV027 (β-arrestin biased agonists) at 90s, 10min, and 60min after stimulation. We systematically analyzed the kinetics of AT1R trafficking and determined that distinct ligands lead AT1R to different cellular compartments for downstream signaling activation and receptor degradation/recycling. Distinct proximity labelling of proteins from a number of functional classes, including GTPases, adaptor proteins, and kinases were activated by different ligands suggesting unique signaling and physiological roles of the AT1R. Ligands within the same class, i.e. either G protein-biased or -arrestin-biased, shared high similarity in their labelling profiles. Comparison between ligand classes revealed distinct signaling activation such as greater labeling by G protein biased ligands on ESCRT-0 complex proteins that act as sorting machinery for ubiquitinated proteins. Our study provides a comprehensive analysis of AT1R receptor trafficking kinetics and signaling activation profiles induced by distinct classes of ligands.

2021-03-25 | PXD023814 | Pride

Exercise Training Remodels Inguinal White Adipose Tissue Through Adaptations in Innervation, Vascularization and the Extracellular Matrix

Project description:Inguinal white adipose tissue (iWAT) is essential for the beneficial effects of exercise training on metabolic health. The underlying mechanisms for these effects are not fully understood and here, we test the hypothesis that exercise training results in a more favorable iWAT structural phenotype. Using biochemical, imaging, and multi-omics analyses we find that 11-days of wheel running in male mice causes profound iWAT remodeling including decreased extracellular matrix (ECM) deposition, increased vascularization and innervation. We identify adipose stem cells as one of the main contributors to training-induced ECM remodeling, show that the PRDM16 transcriptional complex is necessary for iWAT remodeling and beiging, and discover neuronal growth regulator 1 (NEGR1) as a link between PRDM16 and neuritogenesis. Moreover, we find that training causes a shift from hypertrophic to insulin-sensitive adipocyte subpopulations. Exercise training leads to remarkable adaptations to iWAT structure and cell-type composition that can confer beneficial changes in tissue metabolism.

2023-10-24 | PXD040894 | Pride

Cysteine 253 of UCP1 regulates energy expenditure and adipose tissue inflammation

Project description:Uncoupling protein 1 (UCP1) is thought to be a major regulator of whole-body energy expenditure and metabolic homeostasis. However, the widely employed UCP1 loss of function model has recently been shown to have destructive effects on the entire electron transport chain of thermogenic fat. As such, the role of UCP1 in metabolic regulation in vivo remains unclear. We recently identified cysteine-253 as an allosteric site on UCP1 that elevates protein activity upon covalent modification. Here we examine the physiological importance of this site through the generation of a UCP1 cysteine-253 null mouse (UCP1 C253A), the first genetic model for selective disruption of UCP1 in vivo. UCP1 C253A mice exhibit significantly compromised thermogenic responses but display no measurable effect on fat accumulation in an obesogenic environment. Unexpectedly, instead we find that lack of cysteine-253 results in substantial immune cell infiltration and inflammatory pathology in adipose tissues of male, but not female mice. Together, our results establish the UCP1 cysteine-253 activation site as a regulator of acute thermogenesis and sex-dependent adipose tissue inflammation.

2021-12-15 | PXD029270 | Pride

Using CC strains to dissect the genetic regulation of the proteome

Project description:Proteins perform a wide range of biological functions and are often exhibit to multi-factorial regulatory patterns. To better understand the roles of genetics and sex in protein regulation, we quantitatively analyze and compare the liver proteomes from related genetically diverse mouse populations, representing inbred genetic backgrounds.

2021-07-29 | PXD018886 | Pride

Altered patterns of global protein synthesis and translational fidelity in RPS15-mutated chronic lymphocytic leukemia

Project description:Genomic studies have recently identified RPS15 as a new driver gene in aggressive and chemorefractory cases of chronic lymphocytic leukemia (CLL). RPS15 encodes a ribosomal protein whose conserved C-terminal domain extends into the decoding center of the ribosome. We demonstrate that mutations in highly conserved residues of this domain affect both protein stability —by increasing its ubiquitin-mediated degradation— and cell proliferation rates. On the other hand, we show that mutated RPS15 can be loaded into the ribosomes, directly impacting on global protein synthesis and/or translational fidelity in a mutation-specific manner. Quantitative mass-spectrometry analyses suggest that RPS15 variants may induce additional alterations in the translational machinery as well as a metabolic shift at the proteome level in both HEK293T and MEC-1 cells. These results indicate that CLL-related RPS15 mutations might act following patterns known for other ribosomal diseases, likely switching from a hypo- to a hyperproliferative phenotype driven by mutated ribosomes. In this scenario, loss of translational fidelity causing altered cell proteostasis can be proposed as a new molecular mechanism involved in CLL pathobiology.

2019-09-09 | PXD010924 | Pride

OmicsDI is part of the ELIXIR infrastructure

OmicsDI is an Elixir interoperability service. Learn more ›

Tweets

OmicsDI Databases

PRIDE
PeptideAtlas
MassIVE
JPOST Repository
Physiome Model Repository

EGA
EVA
ENA
LINCS
PAXDB
Cell Collective

MetaboLights
Metabolomics Workbench
MetabolomeExpress
GNPS
BioModels
FAIRDOMHub

ArrayExpress
dbGaP
ExpressionAtlas
GEO
NODE

Information

Databases
Help
API
Contact us
Code on GitHub
Terms of use
Submit Data