CCL22 chemokine mutations drive natural killer cell lymphoproliferative disease by biasing GPCR signaling
Ontology highlight
ABSTRACT:
PROVIDER: EGAS00001006009 | EGA |
REPOSITORIES: EGA
Similar Datasets
Project description:Chemokine receptors (CKRs), a class of G protein-coupled receptors (GPCRs), interact with transducers like G proteins and β-arrestins. Many chemokines act as “biased agonists” that activate certain transducers over others. There has been limited success in pharmacologically targeting CKRs, with little evidence that differential receptor phosphorylation, or “phosphorylation barcodes,” direct biased responses. Here, we used mass spectrometry to demonstrate that CXCR3 chemokines generate different phosphorylation barcodes associated with differential activation of transducers. Chemokine stimulation resulted in distinct changes throughout the kinome in global phosphoproteomic studies. Mutation of CXCR3 phosphosites altered β-arrestin conformation and activation in molecular dynamics simulations. T-cells expressing phosphorylation-deficient CXCR3 mutants resulted in agonist- and receptor-specific chemotactic profiles not completely explained by engagement of G proteins and β-arrestins. Our results demonstrate that CXCR3 chemokines act as biased agonists through differential encoding of phosphorylation barcodes, and highlight the limitations of assessing GPCR physiology with proximal effector activity alone.
2023-05-24 | PXD034033 | JPOST Repository
Project description:A key requisite for the success of a dendritic cell (DC)-based vaccine in treating malignancies is the capacity of the DCs to attract immune effector cells for further interaction and activation, considering crosstalk with DCs is partially regulated by cell-contact-dependent mechanisms. Although critical for therapeutic efficacy, immune cell recruitment is a largely overlooked aspect regarding optimization of DC therapy. In this paper we examine if the so-called interleukin (IL)-15 DC vaccine provides a favorable chemokine milieu for recruiting T cells, natural killer (NK) cells and gamma delta (γδ) T cells, in comparison with the IL-4 DCs used routinely for clinical studies, as well as the underlying mechanisms of immune cell attraction by IL-15 DCs. Chemokine signaling is studied both at the RNA level, using microarray data of mature DCs, and functional level, by means of a transwell chemotaxis assay. Important to note, the classic IL-4 DC vaccine falls short to attract the required immune effector lymphocytes, whereas the IL-15 DCs provide a favorable chemokine milieu for recruiting all cytolytic effector cells. The elevated secretion of the chemokine (C-C motif) ligand 4 (CCL4), also known as macrophage inflammatory protein-1β (MIP-1β), by IL-15 DCs underlies the enhanced migratory responsiveness of T cells, NK cells and γδ T cells. Namely, neutralizing its receptor CCR5 resulted in a significant drop in migration of the aforementioned effector cells towards IL-15 DCs. These findings should be kept in mind in the design of future DC-based cancer vaccines.
2016-03-17 | GSE79184 | GEO
Project description:G protein-coupled receptors (GPCRs) interact with many transducers like G proteins and β-arrestins. Some GPCR agonists act as “biased agonists” which preferentially activate specific signaling transducers over others, leading to unique signaling profiles. The chemokine system, a subfamily of GPCRs that plays a critical role in inflammatory diseases, serves as an endogenous example of biased agonism where over 50 different chemokines ligands and 20 receptors interact promiscuously. In this study, we sought to determine the three different chemokines of the chemkoine receptor CXCR3 generate different transcriptional responses in primary CD8+ T cells. Using RNAseq on CD8+ T cells stimulated with either vehicle control, CXCL9, CXCL10, or CXCL11, the endogenous chemokines of CXCR3, we found that the CXCR3 chemokines promoted unique transcriptional responses that are predicted to differentially regulate inflammatory pathways. We observed significant changes in global transcriptional activation, detecting approximately 48000 transcripts, 887 of which varied by chemokine treatment. There was a high degree of replicability between biological replicates. The overwhelming majority of differentially expressed genes (DEGs) increased in transcript level following chemokine treatment. Compared to vehicle control, CXCL11 demonstrated the largest number of DEGs. Importantly, CXCL11 and CXCL10 demonstrate unique transcriptional profiles where the majority of DEGs were only found following treatment with each specific chemokine, rather than being shared across chemokines. These data contrast with that observed at CXCL9 – although it promoted a significant amount of transcriptional regulation, approximately 66% of CXCL9-induced DEGs were shared with CXCL11 and/or CXCL10.
2022-07-23 | GSE192679 | GEO
Project description:Many G protein-coupled receptors (GPCRs) are found to homo- or hetero-oligomerize, but how and why GPCRs associate remains controversial. The class A chemokine receptors CCR5 and CXCR4 both homo- and heterodimerize with each other, and crystal structures of CXCR4 in inactive conformations have captured dimeric organization. By selecting libraries of CCR5 and CXCR4 variants based on bimolecular fluorescence complementation, we determine how nearly every single amino acid substitution effects homo-associations. We find three mechanisms for chemokine receptor association: (i) non-specific aggregation in the membrane phase enhanced by destabilizing structural mutations, (ii) specific protein-protein dimerization interfaces, and (iii) motifs in the cytoplasmic tails that are hypothesized to promote lipid raft localization, thereby bringing receptors close together at high density. We identify mutations that tease apart the effects of these respective mechanisms, and show that specific dimer organization, despite reducing agonist binding, is necessary for active signaling within the cell.
2020-05-01 | GSE125426 | GEO
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
Project description:As the principal effector cell population of the innate immune system, NK cells may make critical contributions to natural, immune-mediated control of HIV-1 replication. Using genome-wide assessments of activating and inhibitory epigenetic chromatin features, we here demonstrate that cytotoxic NK (cNK) cells from elite controllers (ECs) frequently display elevated activating histone modifications at the IL-2/IL-15 receptor β chain and the BCL-2 gene loci. These epigenetic changes translated into increased responsiveness of cNK cells to paracrine IL-15 secretion, which coincided with higher levels of IL-15 transcription by myeloid dendritic cells in ECs. The distinct immune crosstalk between these two innate immune cell populations resulted in improved IL-15-dependent cNK cell survival, paired with a metabolic profile biased towards IL-15-mediated glycolytic activities. Together, these results suggest that cNK cells from ECs display an epigenetically-programmed IL-15 response signature, and support the emerging role of innate immune pathways in natural, drug-free control of HIV-1.
2023-12-06 | GSE232915 | GEO
Project description:As the principal effector cell population of the innate immune system, NK cells may make critical contributions to natural, immune-mediated control of HIV-1 replication. Using genome-wide assessments of activating and inhibitory epigenetic chromatin features, we here demonstrate that cytotoxic NK (cNK) cells from elite controllers (ECs) frequently display elevated activating histone modifications at the IL-2/IL-15 receptor β chain and the BCL-2 gene loci. These epigenetic changes translated into increased responsiveness of cNK cells to paracrine IL-15 secretion, which coincided with higher levels of IL-15 transcription by myeloid dendritic cells in ECs. The distinct immune crosstalk between these two innate immune cell populations resulted in improved IL-15-dependent cNK cell survival, paired with a metabolic profile biased towards IL-15-mediated glycolytic activities. Together, these results suggest that cNK cells from ECs display an epigenetically-programmed IL-15 response signature, and support the emerging role of innate immune pathways in natural, drug-free control of HIV-1.
2023-12-06 | GSE232914 | GEO
Project description:The ubiquitin (Ub) proteasome system (UPS) performs the covalent attachment of lysine 48-linked poly-Ub chains to substrate proteins, thereby targeting them for degradation, while deubiquitylating enzymes (DUBs) reverse this process. This post-translational modification system regulates many processes in the innate and adaptive immune system. Here we show that loss of one of the most highly expressed DUBs, Otub1, results in changes in splenic B cell subsets, leading to a significant increase in marginal zone and transitional B cells and a decrease in follicular B cells. We demonstrate that Otub1 interacts with and modulates the ubiquitylation status of the heterotrimeric G-protein g-subunit Gng2, thereby regulating Gng2 stability. Proximal mapping of Gng2 revealed an enrichment in partners associated with cell migration and chemokine signaling. Indeed, Otub1-deficient B cells exhibited sustained chemokine receptor signaling and increased chemokine responsiveness towards Cxcl12, Cxcl13 and S1P in vitro, which manifested in vivo as a defect in the localization of splenic B cells. Together, our data establishes Otub1 as a novel regulator of G-protein coupled receptor signaling (GPCR) in B cells, altering their positioning and differentiation.
2023-02-08 | MSV000091229 | MassIVE
Project description:The transcription expressions of gout goslings in renal tissues was significantly different from that of healthy goslings. With P <0.05 and |log2(fold change)| >1 as the selection standards, 1749 differential expression genes were found. Among these, 501 genes were up-regulated and 1248 genes were down-regulated in the gout group. The gene ontology (GO) search revealed many significant terms, including chemokine activity, T cell receptor binding, antigen binding, immune response, G-protein coupled receptor signaling pathway, chemokine-mediated signaling pathway, inflammatory response and so on. The Kyoto Encyclopedia of Genes and Genomes (KEGG) selected the cytokine-cytokine receptor interaction, intestinal immune network for IgA production, cell adhesion molecules. In conclusion, the kidney injuries in gout goslings is closely related to immune response, inflammatory response and cell adhesion processes.
2023-02-04 | GSE144723 | GEO
Project description:Neuroblastoma is the most common extracranial solid childhood tumor with clinical manifestations ranging from benign tumors that spontaneously regress to highly aggressive metastatic disease. Unfortunately, there is no therapy known to be curative for high-risk neuroblastoma. The calcium-sensing receptor (CaSR) is a G protein-coupled receptor that senses plasmatic fluctuation in the extracellular concentration of calcium and plays a key role in maintaining calcium homeostasis. We have previously reported that this receptor exhibits tumor suppressor properties in neuroblastoma. The activation of CaSR with cinacalcet, a positive allosteric modulator of CaSR, reduces neuroblastoma tumor-growth by promoting differentiation, ER stress and apoptosis. However, these promising results came with an associated side effect, since cinacalcet exposure resulted in hypocalcemia. Based on the biased signaling shown by calcimimetics, we aimed to identify a new drug that might exert tumor-growth inhibition similar to cinacalcet without affecting plasma calcium levels. We identified a structurally different calcimimetic AC-265347 as a promising therapeutic agent for neuroblastoma, since it reduced tumor-growth by induction of differentiation, without affecting plasma calcium levels. Microarrays analysis suggested biased allosteric modulation of the CaSR signaling by both calcimimetics towards distinct intracellular pathways since no upregulation of genes involved in calcium signaling and ER stress were observed in PDX models exposed to AC-265347. Moreover, the most significant upregulated biological pathways promoted by AC-265347 were linked to RHO GTPases signaling. AC-265347 also up-regulated cancer testis antigens (CTAs), thus providing new opportunities for CTA-based immunotherapies. Taken together, this study helps to shed light about the importance of the biased allosteric modulation when targeting GPCRs in cancer. More importantly, the capacity of AC-265347 to promote differentiation of malignant neuroblastoma cells provides new opportunities, alone or in combination with other drugs, to control minimal residual disease and to prevent relapse in patients affected with neuroblastoma.
2022-04-27 | GSE195577 | GEO