Innate immune function of galectin-1 as a DAMP
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ABSTRACT:
ORGANISM(S): Mus musculus
PROVIDER: GSE140892 | GEO | 2020/10/29
REPOSITORIES: GEO
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Project description:Human monocyte derived dendritic cells matured via galectin-1 or LPS. Experiment Overall Design: 4 conditions with 3 replicates of each include control or intreated immature MDDCS, galectin-1 treated MDDCs, LPS treated MDDCs, and vehicle control MDDCs. (each replicate is from a distinct DONOR). Dendritic cells (DCs) are potent mediators of the immune response, and can be activated by exogenous pathogen components. Galectin-1 is a member of the conserved beta-galactoside-binding lectin family that binds galactoside residues on cell surface glycoconjugates. Galectin-1 is known to play a role in immune regulation via action on multiple immune cells. However, its effects on human DCs are unknown. In this study, we show that galectin-1 induces a phenotypic and functional maturation in human monocyte-derived DCs (MDDCs) similar to but distinct from the activity of the exogenous pathogen stimuli, LPS. Immature human MDDCs exposed to galectin-1 up-regulated cell surface markers characteristic of DC maturation (CD40, CD83, CD86, and HLA-DR), secreted high levels of IL-6 and TNF-alpha, stimulated T cell proliferation, and showed reduced endocytic capacity, similar to LPS-matured MDDCs. However, unlike LPS-matured DCs, galectin-1-treated MDDCs did not produce the Th1-polarizing cytokine IL-12. Microarray analysis revealed that in addition to modulating many of the same DC maturation genes as LPS, galectin-1 also uniquely up-regulated a significant subset of genes related to cell migration through the extracellular matrix (ECM). Indeed, compared with LPS, galectin-1-treated human MDDCs exhibited significantly better chemotactic migration through Matrigel, an in vitro ECM model. Our findings show that galectin-1 is a novel endogenous activator of human MDDCs that up-regulates a significant subset of genes distinct from those regulated by a model exogenous stimulus (LPS). One unique effect of galectin-1 is to increase DC migration through the ECM, suggesting that galectin-1 may be an important component in initiating an immune response.
2007-10-26 | E-GEOD-4984 | biostudies-arrayexpress
Project description:Galectins constitute a family of ß-galactoside binding proteins that translate sugar-encoded signals of cell surface glycoconjugates into biological effects. The expression pattern of different human galectins changes during tissue development and is altered at sites of inflammation and tumor. Galectins have been known to be involved in colorectal cancer development, progression and metastasis. Galectin-4 has already been reported to function as tumor suppressor in this type of malignancy. However, its detailed impact on the tumor phenotype is still unknown. Our previous work indicates that galectin-4 inhibits cell proliferation and induces morphological changes in analyzed human colon cancer cell lines, including LS 180.
2016-12-23 | PXD003489 | Pride
Project description:The multifunctional -galactoside-binding protein galectin-3 is found in many distinct subcellular compartments including the cell nucleus. Expression and distribution of galectin-3 between the cell nucleus and the cytosol changes during cell differentiation and cancer development. Nuclear functions of galectin-3 and how they contribute to tumorigenesis are not understood. In order to identify nuclear galectin-3 interaction partners, we used affinity chromatography and co-immunoprecipitation. Spatial proximity in the nucleus was assessed by immunofluorescence and proximity ligation assay. We also investigated the function of galectin-3 on mRNA-export by fluorescence in situ hybridization and on mRNA-processing by RNA-sequencing.
2016-06-07 | E-MTAB-4783 | biostudies-arrayexpress
Project description:Hyperactive angiogenesis contributes to the immunosuppressive microenvironment important for immunotherapy, and LGALS1-encoed galectin-1 can trigger vascular signaling programs and mediate anti-angiogenic treatment response. However, the mechanism of galectin-1 regulation of angiogenesis is poorly understood. Previous mRNA interactome studies suggested that galectin-1 associated with mRNAs. In this study, we applied the iRIP-seq methodology, an unbiased genome-wide approach to study the RNA binding profiles of galectin-1. The results demonstrate that galectin-1 interacted with a large population of mRNAs with a preferred location towards stop codon, and preferred motifs of UGCA/UGGA and GAGCAG motifs. Galectin-1-bound mRNAs are enriched in cell cycle control and diverse basic biological processes, including its previously reported protein targets H-Ras and also T cell receptors TLR6. Glectin-1 significantly binds to genes in angiogenesis, which included the key pro-angiogenic growth factor VEGFA, angiogenic regulators EGR1 and LAMA5, suggesting that galectin-1 may regulate via its mRNA binding activity. The presented results uncover an previously unrecognized mRNA binding activity of galectin-1; further pursue of this activity could lead to knowledge important for developing therapeutic strategies against cancer and other diseases involved in aberrant angiogenesis.
2021-10-14 | GSE147565 | GEO
Project description:Background: Angiogenesis is an essential step for tissue development and its dysregulation is associated with various diseases, including moyamoya disease. Among the regulators of angiogenesis, galectin-1 encoded by LGALS1, plays essential roles, but the underlying mechanisms need to be further expounded. In this study, we systematically investigated the potential targets of galectin-1 by silencing LGALS1 (siLGALS1) in human umbilical vein endothelial cells (HUVECs) and performing whole transcriptome sequencing (RNA-seq) experiments. We also integrated galectin-1-interacting RNA data to explore how galectin-1 regulates gene expression and alternative splicing. Results: By systematical analysis, we found siLGALS1 treatment significantly regulated 1451 differentially expressed genes (DEGs), including 604 up-regulated DEGs and 847 down-regulated DEGs. The down-regulated DEGs were significantly enriched in angiogenesis and inflammatory response pathways. The involved genes included CCL2, GJA5, CALCRL, ACKR3, HEY1, AQP1, CD34, ECM1, RAMP2, and SELP, which were also validated by RT-qPCR experiment. We also analyzed the dysregulated alternative splicing (AS) profile by siLGALS1, and found siLGALS1 had obvious bias for dysregulated AS types, preferring to promote exon skipping and intron retention, and inhibit cassette exon events. Interestingly, we found the regulated AS genes (RASGs) were enriched in focal adhesion and VEGF signaling pathway, which were highly related to angiogenesis. Finally, we found hundreds of RASGs were also bound by galectin-1 using the published iRIP-seq data of galectin-1, including RASGs from angiogenesis pathway. Conclusions: In summary, our results demonstrated that galectin-1 could regulate angiogenesis-related genes at transcriptional and post-transcriptional levels, which is associated its RNA binding ability in HUVECs. The discovery extends our understanding on the functions and molecular mechanisms of galectin-1 during the development of angiogenesis, which could be served as a therapeutic option in anti-angiogenic treatment in future.
2022-12-23 | GSE201537 | GEO
Project description:Galectin-3 is a carbohydrate binding protein implicated in cell-cell interaction and cell growth. Interestingly, recent studies suggest that galectin-3 is involved in cell metabolism and linked to diabetes and cancer. How galectin-3 might act as a diabetogenic and tumorogenic factor remains to be investigated. Here we report that intracellular galectin-3 is physically associated with Rag GTPases and Ragulator of the mTORC1 signaling machinery on lysosomes. We show that galectin-3 senses lipopolysaccharide (LPS) to facilitate the interaction of Rag GTPases and Ragulator, leading to activation of Rag GTPases thus lysosomal loading of mTOR and activation of mTORC1. Integrative genomics and transcriptomics analyses reveal that the LPS/galectin-3-Rag GTPases/Ragulator-mTORC1 axis regulates a cohort of genes including GLUT1 (glucose transporter member 1) that functions in glucose uptake and glycolysis and HK2 (hexokinase 2) and PKM2 (pyruvate kinase M2) that catalyze the first and last step of glycolysis, respectively. Indeed, galectin-3 deficiency severely compromises LPS-promoted glycolysis. Importantly, in diabetes patients, the expression of HK2 was significantly reduced, and in hepatocellular carcinoma (HCC), thyroid cancer, and prostate cancer, galectin-3 is highly expressed, and its level of expression is positively correlated with that of HK2 and PKM2 and negatively correlated with the prognosis of HCC patients. Our study unravels that galectin-3 is a sensor of LPS, an important modulator of the mTORC1 signaling, and a critical regulator of glucose metabolism, adding to the understanding of diabetogenesis and tumorigenesis.
2022-10-25 | GSE211784 | GEO
Project description:Infection by the Gram-negative bacterium Pseudomonas aeruginosa is common in hospitalized immunocompromised as well as immunocompetent ventilated patients and is often life-threatening because of resistance of the bacteria to antibiotics. This prompts the question whether the host’s immune system can be educated to combat this bacterium. Bacterial lipopolysaccharide (LPS) is known to promote host resistance to bacterial infections although an understanding of the underlying mechanism is lacking. Here we show that prior exposure to a single low dose of LPS protects mice from a lethal infection by P. aeruginosa. These mice displayed expansion of a neutrophil and an interstitial macrophage population that were barely detectable in mice that did not receive LPS prior to infection. Both cell populations were distinguishable from other immune cell populations by being enriched in gene sets that included phagocytosis- and cell-killing-associated genes. The cell killing gene set in the neutrophil population uniquely expressed Lgals3, which encodes the multifunctional antibacterial protein, galectin-3. Intravital imaging of neutrophils for bacterial phagocytosis, assessment of bacterial killing and neutrophil-associated galectin-3 protein levels together with use of galectin-3-deficient mice collectively highlight neutrophils and galectin-3 as central players in LPS-mediated protection. Interrogating the relevance of these findings in hospitalized patients with acute respiratory failure revealed significantly higher galectin-3 levels in endotracheal aspirates (ETAs) of survivors compared to non-survivors, galectin-3 levels strongly correlating with a neutrophil signature in the ETAs. Taken together, our study provides impetus to harnessing the potential of galectin-3-expressing neutrophils to protect the lung from lethal infections and respiratory failure.
2024-04-15 | GSE237646 | GEO
Project description:Innate immune function of galectin-1 as a DAMP
| PRJNA591290 | ENA
Project description:Identification of interactors is a major attempt in cell biology. Not only protein-protein but also protein-carbohydrate interactions are of high relevance for signal transduction in biological systems. Here we aim to identify novel interacting binding partners for the β-galactoside-binding proteins Galectin-1 (Gal-1) and Galectin-3 (Gal-3) in context of the eye disease proliferative vitreoretinopathy (PVR). PVR is one of the most common failures after retinal detachment surgeries and is characterized by the migration, adhesion and epithelial-to-mesenchymal transition (EMT) of retinal pigment epithelial cells (RPE) and the subsequent formation of sub- and epiretinal fibrocellular membranes. Gal-1 and Gal-3 bind in a dose- and carbohydrate-dependent manner to mesenchymal RPE cells and inhibit cellular processes like attachment and spreading. Yet knowledge about glycan-dependent interactors of Gal-1 and Gal-3 on RPE cells is very limited, although this is a prerequisite to unravel the influence of galectins on distinct cellular processes in RPE cells. In this approach, we identified by galectin pull-down experiments and quantitative proteomic screening 131 Galectin-3 and 15 Galectin-1 interactors. They mainly play a role in multiple binding processes and are mostly membrane proteins. Here we focused on two novel identified interactors of Gal-1 and Gal-3 in the context of PVR: the low-density lipoprotein receptor LRP1 and the platelet-derived growth factor receptor beta PDGFRB. We observed crosslinking and lattice formation of exogenous Gal-1 and Gal-3 with LRP1/PDGFRB and ITGB1 on the cell surface of human RPE cells. Weaker binding of Gal-1 and Gal-3 on these interactors and no lattice formation on the cell surface was seen, when complex-type-N-glycosylation was inhibited by treatment of the cells with Kifunensine. In conclusion, the identified specific glycoprotein ligands for Gal-1 and Gal-3 give us new insights in the highly specific binding of galectins to dedifferentiated RPE cells and the resulting prevention of PVR-associated cellular events.
2017-06-06 | PXD005461 | Pride
Project description:Galectin-3 is a glycan-binding protein (GBP) that binds β -galactoside glycan structures to orchestrate a variety of important biological events, including the activation of hepatic stellate cells and regulating immunological responses. While the requisite glycan epitopes needed to bind galectin-3 have long been elucidated, the cellular glycoproteins that bear these glycan signatures remain unknown. Given the importance of the three-dimensional arrangement of glycans in dictating GBP interactions, strategies that allow the identification of GBP receptors in live cells, where the native glycan presentation and glycoprotein expression are preserved, possess significant advantages over static and artificial systems. Here, we describe the integration of a proximity labeling method and quantitative mass spectrometry to map the glycan and glycoprotein interactors for galectin-3 in live human hepatic stellate cells and peripheral blood mononuclear cells. Understanding the identity of the glycoproteins and defining the structures of the glycans will empower efforts to design and develop selective therapeutics to mitigate galectin-3-mediated biological events.
2021-06-16 | PXD021622 | Pride