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  • 1
    Publication Date: 2018-01-04
    Description: O -glycosylation is a post-translational modification of proteins crucial to molecular mechanisms in health and disease. O -glycans are typically highly heterogeneous. The involvement of specific O -glycan sequences in many bio-recognition systems is yet to be determined because of a lack of efficient methodologies. We describe here a targeted microarray approach: O -glycome beam search that is both robust and efficient for O -glycan ligand-discovery. Substantial simplification of the complex O -glycome profile and facile chromatographic resolution is achieved by arraying O -glycans as branches, monitoring by mass spectrometry, focusing on promising fractions, and on-array immuno-sequencing. This is orders of magnitude more sensitive than traditional methods. We have applied beam search approach to porcine stomach mucin and identified extremely minor components previously undetected within the O -glycome of this mucin that are ligands for the adhesive proteins of two rotaviruses. The approach is applicable to O -glycome recognition studies in a wide range of biological settings to give insights into glycan recognition structures in natural microenvironments.
    Print ISSN: 1535-9476
    Electronic ISSN: 1535-9484
    Topics: Biology , Medicine
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  • 2
    Publication Date: 2018-12-02
    Description: Production of 25-hydroxycholesterol (25HC), a potent inhibitor of viral infection, is catalyzed by cholesterol 25-hydroxylase (CH25H). We previously reported that 25HC induced CH25H expression in a liver X receptor (LXR)-dependent manner, implying that LXR can play an important role in antiviral infection. In this study, we determined that activation of LXR by 25HC or synthetic ligands [T0901317 (T317) or GW3965] inhibited infection of herpes simplex virus type 1 (HSV-1) or MLV-(VSV)-GFP in HepG2 cells or RAW 264.7 macrophages. Genetic deletion of LXRα, LXRβ, or CH25H expression in HepG2 cells by CRISPR/Cas9 method increased cell susceptibility to HSV-1 infection and attenuated the inhibition of LXR on viral infection. Lack of interferon (IFN)- expression also increased cell susceptibility to viral infection. However, it attenuated, but did not block, the inhibition of LXR on HSV-1 infection. In addition, expression of CH25H, but not IFN-, was inversely correlated to cell susceptibility to viral infection and the antiviral actions of LXR. Metabolism of 25HC into 25HC-3-sulfate (25HC3S) by cholesterol sulfotransferase-2B1b moderately reduced the antiviral actions of 25HC because 25HC3S is a weaker inhibitor of HSV-1 infection than 25HC. Furthermore, administration of T317 to BALB/c mice reduced HSV-1 growth in mouse tissues. Taken together, we demonstrate an antiviral system of 25HC with involvement of LXR activation, interaction between CH25H and IFN-, and 25HC metabolism.
    Print ISSN: 0022-2275
    Electronic ISSN: 1539-7262
    Topics: Biology , Chemistry and Pharmacology , Medicine
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  • 3
    Publication Date: 2018-10-11
    Description: Salmonella enterica serovar Typhimurium ( S. Typhimurium) is one of the most used models for bacterial pathogenesis and successful infection requires its adaptation to the low oxygen environment in host gastrointestinal tracts. Central to this process is the Arc ( a erobic r espiratory c ontrol) two-component regulatory system that contains a sensor kinase ArcB and a response regulator ArcA. Nevertheless, a comprehensive profile of the ArcA regulon on the proteome level is still lacking in S. Typhimurium. Here we quantitatively profiled Salmonella proteome during anaerobiosis in an arcA -deleting mutant compared with its parental strain. In addition to known processes under its control, notably we found that ArcA represses ethanolamine utilization by directly binding to the promoter region of the eut operon. Furthermore, we found opposing changes of several bacterial genes on the protein and transcript levels in the arcA -deleting mutant including the virulence genes of Salmonella pathogenicity island 1 (SPI-1), thereby indicating potentially prevalent post-transcriptional regulatory mechanisms. Altogether, our study provides important new insights into ArcA-dependent bacterial physiology and virulence during Salmonella anaerobiosis.
    Print ISSN: 1535-9476
    Electronic ISSN: 1535-9484
    Topics: Biology , Medicine
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  • 4
    Publication Date: 2018-04-02
    Description: The systematic investigation of gene mutation and expression is important to discover novel biomarkers and therapeutic targets in cancers. Here, we integrated genomics, transcriptomics, proteomics, and metabolomics to analyze three hepatocellular carcinoma (HCC) cell lines with differential metastatic potentials. The results revealed the profile of the prometastasis metabolism potentially associated with HCC metastasis. The multiomic analysis identified 12 genes with variations at multiple levels from three metabolic pathways, including glycolysis, starch, and sucrose metabolism, and glutathione metabolism. Furthermore, uridine diphosphate (UDP)-glucose pyrophosphorylase 2 (UGP2), was observed to be persistently up-regulated with increased metastatic potential. UGP2 overexpression promoted cell migration and invasion and enhanced glycogenesis in vitro . The role of UGP2 in metastasis was further confirmed using a tumor xenograft mouse model. Taken together, the compendium of multiomic data provides valuable insights in understanding the roles of shifted cellular metabolism in HCC metastasis.
    Print ISSN: 1535-9476
    Electronic ISSN: 1535-9484
    Topics: Biology , Medicine
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  • 5
    Publication Date: 2018-03-06
    Description: Cholesterol 25-hydroxylase (CH25H) catalyzes the production of 25-hydroxycholesterol (25-HC), an oxysterol that can play an important role in different biological processes. However, the mechanisms regulating CH25H expression have not been fully elucidated. In this study, we determined that CH25H is highly expressed in mouse liver and peritoneal macrophages. We identified several liver X receptor (LXR) response elements (LXREs) in the human CH25H promoter. In HepG2 cells, activation of LXR by 25-HC or other oxysterols and synthetic ligands [T0901317 (T317) and GW3965] induced CH25H protein expression, which was associated with increased CH25H mRNA expression. 25-HC or T317 activated CH25H transcription in an LXRE-dependent manner. Thus, high-expressing LXRα or LXRβ activated CH25H expression, and the activation was further enhanced by LXR ligands. In contrast, inhibition of LXRα/β expression attenuated 25-HC or T317-induced CH25H expression. Deficiency of interferon expression reduced, but did not block, LXR ligand-induced hepatic CH25H expression. Activation of LXR also substantially induced macrophage CH25H expression. In vivo, administration of GW3965 to mice increased CH25H expression in both liver and peritoneal macrophages. Taken together, our study demonstrates that 25-HC can activate CH25H expression in an LXR-dependent manner, which may be an important mechanism to exert the biological actions of 25-HC.
    Print ISSN: 0022-2275
    Electronic ISSN: 1539-7262
    Topics: Biology , Chemistry and Pharmacology , Medicine
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  • 6
    Publication Date: 2018-03-06
    Description: The transport of LDL-derived cholesterol from lysosomes to peroxisomes is facilitated by membrane contacts formed between the lysosomal protein synaptotagmin VII and the peroxisomal lipid phosphatidylinositol 4, 5-bisphosphate [PI(4,5)P 2 ]. Here, we used RNA interference to search for regulators of PI(4,5)P 2 and to study the effects of altered PI(4,5)P 2 homeostasis on cholesterol transport. We found that knockdown of phosphatidylinositol 5-phosphate 4-kinase type-2 α (PIP4K2A) reduced peroxisomal PI(4,5)P 2 levels, decreased lysosome-peroxisome membrane contacts, and increased accumulation of lysosomal cholesterol in human SV-589 fibroblasts. Forced expression of peroxisome-localized, kinase-active PIP4K2A in the knockdown cells reduced cholesterol accumulation, and in vitro addition of recombinant PIP4K2A restored membrane contacts. These results suggest that PIP4K2A plays a critical role in intracellular cholesterol transport by upregulating PI(4,5)P 2 levels in the peroxisomal membrane. Further research into PIP4K2A activity may inform future therapeutic interventions for managing lysosomal storage disorders.
    Print ISSN: 0022-2275
    Electronic ISSN: 1539-7262
    Topics: Biology , Chemistry and Pharmacology , Medicine
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