title: Phosphatidylinositol 3-kinase is involved in Toll-like receptor 4-mediated BST-2/tetherin regulation.
abstract: BST-2 is a virus restriction factor whose expression is principally induced by IFNα through the type I IFN receptor. However, expression of BST-2 is modulated by mitogens, notably the TLR4 agonist - LPS, via mechanisms that are poorly understood. In this study, the role of TLR4 pathway on BST-2 expression was examined. We demonstrate that the TLR4/PI3K signaling pathway regulates both constitutive and LPS-induced BST-2 expression. LPS stimulation induces BST-2 expression in a manner dependent on TLR4/TRIF/IRF3 pathway. Genetic deletion or pharmacological inhibition of signaling through TLR4, as well as, the deletion of the TRIF and IRF3 genes blunts BST-2 induction by LPS. However, MYD88-/- cells have enhanced BST-2 levels and respond to LPS-mediated induction of BST-2. High level of BST-2 in MYD88 null cells is dependent on IFNβ since antibody-mediated neutralization of IFNβ synthesis results in reduced BST-2 levels in these cells. Similar to the effect of MYD88, inhibition of PI3K activity elevates basal BST-2 level and augments LPS-induced BST-2 expression. Importantly, BST-2 regulation via TLR4 and PI3K is transcriptionally controlled. We discovered that actinomycin D-mediated blocking of gene transcription and inhibition of protein synthesis with cycloheximide result in impairment of BST-2 mRNA expression. Taken together, our results demonstrate that activation of TLR4 results in TRIF/IRF3-mediated positive regulation of BST-2 or MYD88/PI3K-directed negative regulation of BST-2. Thus, our findings enlist BST-2 as one of the genes regulated by PI3K downstream of TLR4 and identify the TLR4/PI3K signaling as a novel pathway that controls BST-2 expression.
authors.affiliation: Department of Microbiology, University of Iowa, Carver College of Medicine, Iowa City, IA, United States.
authors.forename: Philip H
authors.initials: PH
authors.lastname: Jones
authors.forename: Chioma M
authors.initials: CM
authors.lastname: Okeoma
mesh_terms: D033942:Adaptor Proteins, Vesicular Transport / Q000235:genetics / Q000276:immunology; D000818:Animals; D015703:Antigens, CD / Q000235:genetics / Q000276:immunology*; D002460:Cell Line; D002478:Cells, Cultured; D015536:Down-Regulation; D017353:Gene Deletion; D050838:Interferon Regulatory Factor-3 / Q000235:genetics / Q000276:immunology; D008070:Lipopolysaccharides / Q000276:immunology*; D008562:Membrane Glycoproteins / Q000235:genetics / Q000276:immunology*; D051379:Mice; D053594:Myeloid Differentiation Factor 88 / Q000235:genetics / Q000276:immunology; D058539:Phosphatidylinositol 3-Kinase / Q000276:immunology*; D015398:Signal Transduction; D051197:Toll-Like Receptor 4 / Q000235:genetics / Q000276:immunology*; D015533:Transcriptional Activation; D000074010:Bone Marrow Stromal Antigen 2
chemical_list: D033942:Adaptor Proteins, Vesicular Transport; D015703:Antigens, CD; D050838:Interferon Regulatory Factor-3; D008070:Lipopolysaccharides; D008562:Membrane Glycoproteins; D053594:Myeloid Differentiation Factor 88; D058539:Phosphatidylinositol 3-Kinase; D051197:Toll-Like Receptor 4; C513868:BST2 protein, mouse; D000074010:Bone Marrow Stromal Antigen 2; C494233:Irf3 protein, mouse; C507780:Myd88 protein, mouse; C476286:Ticam1 protein, mouse; C493487:Tlr4 protein, mouse
keywords: BST-2; LPS; MYD88; PI3K; TLR4; Tetherin