The Impact of β-1,4-Galactosyltransferase V on Microglial Function

Wang, Xiaoyu; Shi, Naiqi; Hui, Meiqi; Jin, Hui; Gao, Shang; Zhou, Qiao; Zhang, Li; Yan, Ming; Shen, Hongmei

doi:10.3389/fncel.2021.723308

Cited by 9 publications

(3 citation statements)

References 56 publications

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“…For instance, several studies have demonstrated the potential of B4GALT5 downregulation to ameliorate insulin resistance by promoting adipogenic commitment and reducing M1 macrophage in ltration [32] . Other researchers have stated that B4GALT5 plays a regulatory role in microglial migration, proliferation, and the release of in ammatory factors [33] . Additionally, B4GALT5 has been shown to regulate the proliferation of breast cancer stem-like cells through glycosylation, speci cally via the Wnt/β-catenin signaling pathway [34] .…”

Section: Discussionmentioning

confidence: 99%

Dysregulation of the miRNA-30a-5p/B4GALT5 axis leads to cell proliferation and is associated with M1 Macrophage Polarization in PNH

zeng

Wang

et al. 2023

Preprint

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Background：MicroRNAs (miRNAs) play diverse roles in various biological processes. However, their role in Paroxysmal Nocturnal Hemoglobinuria (PNH) is not well understood. To investigate the involvement of miRNAs in PNH, we conducted a re-analysis of the GEO database and identified miRNA-30a-5p as the most promising candidate for further mechanism research. Methods: We have constructed a PIGA knock-out K562 cell line and PIGAconditional knock-out mice model by CRISPR/cas9 technology. Furthermore, FACS and colony formation assays were used to clarify proliferative and apoptosis abilities of PNH cells. FACS was used to clarify M1 Macrophage Polarization in mouse bone marrow-derived macrophages (BMDMs). Luciferase assay was used to indicate miRNA target gene. RT-PCR and western blot were used to verify the relationship between miR-30a-5p, B4GALT5 and PI3K/AKT signaling. Results: Our study revealed a significant upregulation of miR-30a-5p in Flaer negative cells compared to Flaer positive cells, in a cohort of 10 PNH patients. Cell colony formation and cell cycle analysis demonstrated that the miRNA-30a-5p mimics group exhibited a higher capacity for proliferation, while the miRNA-30a-5p inhibitor group showed opposite effects. Subsequent luciferase assay results confirmed that miRNA-30a-5p targeted the B4GALT5 gene, which was found to be significantly downregulated in Flaer negative cells from 15 PNH patients. In vitro assays showed that the miRNA-30a-5p/B4GALT5 axis significantly promoted cell proliferation by activating PI3K/AKT signaling. Additionally, our study is the first to describe the polarization state of macrophages in the bone marrow microenvironment of PNH patients, where we observed a higher mean fluorescence intensity (MFI) of CD80 and CD86, markers of M1 macrophages, on macrophages from PNH patients compared to normal controls. Furthermore, siB4GALT5 increased the markers of M1 macrophages in BMDMs, and miRNA-30a-5p inhibitor induced M2-like macrophage polarization, which was markedly reversed in the miRNA-30a-5p inhibition+siB4GALT5 group. Conclusion: Our study has identified that the miRNA-30a-5p targets the B4GALT5 gene, and miRNA-30a-5p/B4GALT5 axis facilitates the proliferation of PNH clones via the PI3K/AKT signaling pathway. Additionally, our findings provide initial evidence that the miRNA-30a-5p/B4GALT5 axis may play a potential role in M1 macrophage polarization in the bone marrow of PNH patients.

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Section: Discussionmentioning

confidence: 99%

Dysregulation of the miRNA-30a-5p/B4GALT5 axis leads to cell proliferation and is associated with M1 Macrophage Polarization in PNH

zeng

Wang

et al. 2023

Preprint

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“…This was accompanied by increased expression of β-1,4-GalT-I and -V mRNAs [ 50 ]. More recent studies have shown that the cortex, hippocampus region, and microglia cells express β-1,4-GalT-V and play an important role in “neuro-inflammation” by way of proliferation and hyper-activation [ 51 ].…”

Section: Inflammation and β-14-galt-vmentioning

confidence: 99%

Central Role of β-1,4-GalT-V in Cancer Signaling, Inflammation, and Other Disease-Centric Pathways

Chatterjee,

Yuan,

Thapa

et al. 2023

IJMS

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UDP-Galactose: Glucosylceramide, β-1,4-Galactose transferase-V (β-1,4-GalT-V), is a member of a large glycosyltransferase family, primarily involved in the transfer of sugar residues from nucleotide sugars, such as galactose, glucose mannose, etc., to sugar constituents of glycosphingolipids and glycoproteins. For example, UDP-Galactose: Glucosylceramide, β-1,4-galactosyltransferase (β-1,4-GalT-V), transfers galactose to glucosylceramide to generate Lactosylceramide (LacCer), a bioactive “lipid second messenger” that can activate nicotinamide adenine dinucleotide phosphate(NADPH) oxidase (NOX-1) to produce superoxide’s (O2−) to activate several signaling pathways critical in regulating multiple phenotypes implicated in health and diseases. LacCer can also activate cytosolic phospholipase A-2 to produce eicosanoids and prostaglandins to induce inflammatory pathways. However, the lack of regulation of β-1,4-GalT-V contributes to critical phenotypes central to cancer and cardiovascular diseases, e.g., cell proliferation, migration, angiogenesis, phagocytosis, and apoptosis. Additionally, inflammation that accompanies β-1,4-GalT-V dysregulation accelerates the initiation and progression of cancer, cardiovascular diseases, as well as inflammation-centric diseases, like lupus erythematosus, chronic obstructive pulmonary disease (COPD), and inflammatory bowel diseases. An exciting development in this field of research arrived due to the recognition that the activation of β-1,4-GalT-V is a “pivotal” point of convergence for multiple signaling pathways initiated by physiologically relevant molecules, e.g., growth factors, oxidized-low density lipoprotein(ox- LDL), pro-inflammatory molecules, oxidative and sheer stress, diet, and cigarette smoking. Thus, dysregulation of these pathways may well contribute to cancer, heart disease, skin diseases, and several inflammation-centric diseases in experimental animal models of human diseases and in humans. These observations have been described under post-transcriptional modifications of β-1,4- GalT-V. On the other hand, we also point to the important role of β-1-4 GalT-V-mediated glycosylation in altering the formation of glycosylated precursor forms of proteins and their activation, e.g., β-1 integrin, wingless-related integration site (Wnt)/–β catenin, Frizzled-1, and Notch1. Such alterations in glycosylation may influence cell differentiation, angiogenesis, diminished basement membrane architecture, tissue remodeling, infiltrative growth, and metastasis in human colorectal cancers and breast cancer stem cells. We also discuss Online Mendelian Inheritance in Man (OMIM), which is a comprehensive database of human genes and genetic disorders used to provide information on the genetic basis of inherited diseases and traits and information about the molecular pathways and biological processes that underlie human physiology. We describe cancer genes interacting with the β-1,4-GalT-V gene and homologs generated by OMIM. In sum, we propose that β-1,4-GalT-V gene/protein serves as a “gateway” regulating several signal transduction pathways in oxidative stress and inflammation leading to cancer and other diseases, thus rationalizing further studies to better understand the genetic regulation and interaction of β-1,4-GalT-V with other genes. Novel therapies will hinge on biochemical analysis and characterization of β-1,4-GalT-V in patient-derived materials and animal models. And using β-1,4-GalT-V as a “bonafide drug target” to mitigate these diseases.

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“…The following supporting information can be downloaded at: . References [ 68 , 69 , 70 , 71 , 72 , 73 , 74 , 75 , 76 , 77 , 78 , 79 , 80 , 81 , 82 , 83 , 84 , 85 , 86 , 104 , 105 , 106 , 107 , 108 , 140 , 141 , 142 , 143 , 144 , 145 , 146 , 147 , 148 , 149 , 150 , 151 , 152 , 153 , 154 , 155 , 156 , 157 , 158 , 159 , 160 , 161 , 162 , 163 , 164 , 165 , 166 , 167 , 168 , 169 , 170 , 171 ,…”

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RNAseq Analysis of FABP4 Knockout Mouse Hippocampal Transcriptome Suggests a Role for WNT/β-Catenin in Preventing Obesity-Induced Cognitive Impairment

Nixon

Bernlohr

et al. 2023

IJMS

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Microglial fatty-acid binding protein 4 (FABP4) is a regulator of neuroinflammation. We hypothesized that the link between lipid metabolism and inflammation indicates a role for FABP4 in regulating high fat diet (HFD)-induced cognitive decline. We have previously shown that obese FABP4 knockout mice exhibit decreased neuroinflammation and cognitive decline. FABP4 knockout and wild type mice were fed 60% HFD for 12 weeks starting at 15 weeks old. Hippocampal tissue was dissected and RNA-seq was performed to measure differentially expressed transcripts. Reactome molecular pathway analysis was utilized to examine differentially expressed pathways. Results showed that HFD-fed FABP4 knockout mice have a hippocampal transcriptome consistent with neuroprotection, including associations with decreased proinflammatory signaling, ER stress, apoptosis, and cognitive decline. This is accompanied by an increase in transcripts upregulating neurogenesis, synaptic plasticity, long-term potentiation, and spatial working memory. Pathway analysis revealed that mice lacking FABP4 had changes in metabolic function that support reduction in oxidative stress and inflammation, and improved energy homeostasis and cognitive function. Analysis suggested a role for WNT/β-Catenin signaling in the protection against insulin resistance, alleviating neuroinflammation and cognitive decline. Collectively, our work shows that FABP4 represents a potential target in alleviating HFD-induced neuroinflammation and cognitive decline and suggests a role for WNT/β-Catenin in this protection.

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The Impact of β-1,4-Galactosyltransferase V on Microglial Function

Cited by 9 publications

References 56 publications

Dysregulation of the miRNA-30a-5p/B4GALT5 axis leads to cell proliferation and is associated with M1 Macrophage Polarization in PNH

Dysregulation of the miRNA-30a-5p/B4GALT5 axis leads to cell proliferation and is associated with M1 Macrophage Polarization in PNH

Central Role of β-1,4-GalT-V in Cancer Signaling, Inflammation, and Other Disease-Centric Pathways

RNAseq Analysis of FABP4 Knockout Mouse Hippocampal Transcriptome Suggests a Role for WNT/β-Catenin in Preventing Obesity-Induced Cognitive Impairment

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