title: Vanadate from air pollutant inhibits hrs-dependent endosome fusion and augments responsiveness to toll-like receptors.
abstract: There is a well-established association between exposure to air pollutants and pulmonary injuries. For example, metals found in ROFA (residual oil fly ash) increase susceptibility of mice as well as humans to microbial infections. In our research, we have found that vanadate substantially increased the response of several Toll-like receptors (TLRs) to stimulation with their ligands. Although vanadate caused generation of reactive oxygen species (ROS), the addition of ROS scavenger N-acetyl cysteine (NAC) had no effect on augmented lipopolysaccharide (LPS) stimulation. We further showed that vanadate inhibits endosome fusion. This effect was determined by measuring the size of endosomes, NF-κB activity and TLR4 degradation in Hrs (hepatocyte growth factor-regulated tyrosine kinase substrate) overexpressed cells. Moreover, we identified the role of Hrs phosphorylation in these processes. Based on our findings, we can conclude that vanadate potentiates TLR4 activity by increasing Hrs phosphorylation status, reducing the size of Hrs/TLR4-positive endosomes and impacting TLR4 degradation, thus contributing to the detrimental effects of air pollutants on human health.
authors.affiliation: National Institute of Chemistry, Laboratory of Biotechnology, Ljubljana, Slovenia.
authors.forename: Mojca
authors.initials: M
authors.lastname: Zelnikar
authors.affiliation: National Institute of Chemistry, Laboratory of Biotechnology, Ljubljana, Slovenia; EN→FIST Centre of Excellence, Ljubljana, Slovenia.
authors.forename: Mojca
authors.initials: M
authors.lastname: Benčina
authors.affiliation: National Institute of Chemistry, Laboratory of Biotechnology, Ljubljana, Slovenia; EN→FIST Centre of Excellence, Ljubljana, Slovenia.
authors.forename: Roman
authors.initials: R
authors.lastname: Jerala
authors.affiliation: National Institute of Chemistry, Laboratory of Biotechnology, Ljubljana, Slovenia; EN→FIST Centre of Excellence, Ljubljana, Slovenia.
authors.forename: Mateja
authors.initials: M
authors.lastname: Manček-Keber
mesh_terms: D000393:Air Pollutants / Q000737:chemistry*; D000818:Animals; D045744:Cell Line, Tumor; D056827:Endosomal Sorting Complexes Required for Transport / Q000235:genetics / Q000378:metabolism*; D011992:Endosomes / Q000187:drug effects* / Q000378:metabolism; D057809:HEK293 Cells; D006801:Humans; D008070:Lipopolysaccharides / Q000494:pharmacology; D051218:Lymphocyte Antigen 96 / Q000235:genetics / Q000378:metabolism; D051379:Mice; D010750:Phosphoproteins / Q000235:genetics / Q000378:metabolism*; D010766:Phosphorylation / Q000187:drug effects; D017382:Reactive Oxygen Species / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D051197:Toll-Like Receptor 4 / Q000235:genetics / Q000378:metabolism*; D014638:Vanadates / Q000737:chemistry / Q000633:toxicity*
chemical_list: D000393:Air Pollutants; D056827:Endosomal Sorting Complexes Required for Transport; C495377:LY96 protein, human; D008070:Lipopolysaccharides; D051218:Lymphocyte Antigen 96; D010750:Phosphoproteins; D017382:Reactive Oxygen Species; D051197:Toll-Like Receptor 4; C096164:hepatocyte growth factor-regulated tyrosine kinase substrate; D014638:Vanadates