title: Heterotrimeric Gi/Go proteins modulate endothelial TLR signaling independent of the MyD88-dependent pathway.
abstract: The innate immune recognition of bacterial lipopolysaccharide (LPS) is mediated by Toll-like receptor 4 (TLR4) and results in activation of proinflammatory signaling including NF-κB and MAPK pathways. Heterotrimeric G proteins have been previously implicated in LPS signaling in macrophages and monocytes. In the present study, we show that pertussis toxin sensitive heterotrimeric G proteins (Gα(i/o)) are involved in the activation of MAPK and Akt downstream of TLR2, TLR3, and TLR4 in endothelial cells. Gα(i/o) are also required for full activation of interferon signaling downstream of TLR3 and TLR4 but are not required for the activation of NF-κB. We find that Gα(i/o)-mediated activation of the MAPK is independent of the canonical MyD88, interleukin-1 receptor-associated kinase, and tumor necrosis factor receptor-associated factor 6 signaling cascade in LPS-stimulated cells. Taken together, the data presented here suggest that heterotrimeric G proteins are widely involved in TLR pathways along a signaling cascade that is distinct from MyD88-TRAF6.
authors.affiliation: Genome Sciences Centre, Vancouver, British Columbia, Canada.
authors.forename: Shauna M
authors.initials: SM
authors.lastname: Dauphinee
authors.forename: Verena
authors.initials: V
authors.lastname: Voelcker
authors.forename: Zinaida
authors.initials: Z
authors.lastname: Tebaykina
authors.forename: Fred
authors.initials: F
authors.lastname: Wong
authors.forename: Aly
authors.initials: A
authors.lastname: Karsan
mesh_terms: D002478:Cells, Cultured; D004789:Enzyme Activation; D051960:GTP-Binding Protein alpha Subunit, Gi2 / Q000235:genetics / Q000378:metabolism*; D017930:Genes, Reporter; D061307:Human Umbilical Vein Endothelial Cells / Q000187:drug effects / Q000276:immunology / Q000378:metabolism*; D006801:Humans; D007113:Immunity, Innate / Q000187:drug effects; D053592:Interleukin-1 Receptor-Associated Kinases / Q000378:metabolism; D008070:Lipopolysaccharides / Q000494:pharmacology; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism; D053594:Myeloid Differentiation Factor 88 / Q000378:metabolism*; D016328:NF-kappa B / Q000378:metabolism; D011070:Poly I-C / Q000494:pharmacology; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D034622:RNA Interference; D015398:Signal Transduction / Q000187:drug effects; D048029:TNF Receptor-Associated Factor 6 / Q000378:metabolism; D013997:Time Factors; D051195:Toll-Like Receptor 2 / Q000378:metabolism; D051196:Toll-Like Receptor 3 / Q000378:metabolism; D051197:Toll-Like Receptor 4 / Q000378:metabolism; D051193:Toll-Like Receptors / Q000378:metabolism*; D014162:Transfection
chemical_list: D008070:Lipopolysaccharides; C507779:MYD88 protein, human; D053594:Myeloid Differentiation Factor 88; D016328:NF-kappa B; C495342:TLR2 protein, human; C495344:TLR3 protein, human; C495345:TLR4 protein, human; D048029:TNF Receptor-Associated Factor 6; D051195:Toll-Like Receptor 2; D051196:Toll-Like Receptor 3; D051197:Toll-Like Receptor 4; D051193:Toll-Like Receptors; D053592:Interleukin-1 Receptor-Associated Kinases; D051057:Proto-Oncogene Proteins c-akt; D020928:Mitogen-Activated Protein Kinases; C498015:GNAI2 protein, human; D051960:GTP-Binding Protein alpha Subunit, Gi2; D011070:Poly I-C