title: The p110δ isoform of the kinase PI(3)K controls the subcellular compartmentalization of TLR4 signaling and protects from endotoxic shock.
abstract: Lipopolysaccharide activates plasma-membrane signaling and endosomal signaling by Toll-like receptor 4 (TLR4) through the TIRAP-MyD88 and TRAM-TRIF adaptor complexes, respectively, but it is unclear how the signaling switch between these cell compartments is coordinated. In dendritic cells, we found that the p110δ isoform of phosphatidylinositol-3-OH kinase (PI(3)K) induced internalization of TLR4 and dissociation of TIRAP from the plasma membrane, followed by calpain-mediated degradation of TIRAP. Accordingly, inactivation of p110δ prolonged TIRAP-mediated signaling from the plasma membrane, which augmented proinflammatory cytokine production while decreasing TRAM-dependent endosomal signaling that generated anti-inflammatory cytokines (interleukin 10 and interferon-β). In line with that altered signaling output, p110δ-deficient mice showed enhanced endotoxin-induced death. Thus, by controlling the 'topology' of TLR4 signaling complexes, p110δ balances overall homeostasis in the TLR4 pathway.
authors.affiliation: Centre for Cell Signaling, Barts Institute of Cancer, Queen Mary, University of London, London, UK.
authors.forename: Ezra
authors.initials: E
authors.lastname: Aksoy
authors.affiliation: Centre for Cell Signaling, Barts Institute of Cancer, Queen Mary, University of London, London, UK.
authors.forename: Salma
authors.initials: S
authors.lastname: Taboubi
authors.affiliation: Institute for Medical Immunology, Free University of Brussels, Gosselies, Belgium.
authors.forename: David
authors.initials: D
authors.lastname: Torres
authors.affiliation: Institute for Medical Immunology, Free University of Brussels, Gosselies, Belgium.
authors.forename: Sandrine
authors.initials: S
authors.lastname: Delbauve
authors.affiliation: Division of Cell and Molecular Biology, Centre for Molecular Microbiology and Infection, Imperial College London, London, UK.
authors.forename: Abderrahman
authors.initials: A
authors.lastname: Hachani
authors.affiliation: Centre for Cell Signaling, Barts Institute of Cancer, Queen Mary, University of London, London, UK.
authors.forename: Maria A
authors.initials: MA
authors.lastname: Whitehead
authors.affiliation: Centre for Cell Signaling, Barts Institute of Cancer, Queen Mary, University of London, London, UK.
authors.forename: Wayne P
authors.initials: WP
authors.lastname: Pearce
authors.affiliation: Centre for Cell Signaling, Barts Institute of Cancer, Queen Mary, University of London, London, UK.
authors.forename: Inma M
authors.initials: IM
authors.lastname: Berenjeno
authors.affiliation: Centre for Cell Signaling, Barts Institute of Cancer, Queen Mary, University of London, London, UK.
authors.forename: Gemma
authors.initials: G
authors.lastname: Nock
authors.affiliation: Division of Cell and Molecular Biology, Centre for Molecular Microbiology and Infection, Imperial College London, London, UK.
authors.forename: Alain
authors.initials: A
authors.lastname: Filloux
authors.affiliation: Department for Molecular Biomedical Research, Unit of Molecular Signal Transduction in Inflammation, VIB, Ghent, Belgium.|Department of Biomedical Molecular Biology, Ghent University, Ghent, Belgium.
authors.forename: Rudi
authors.initials: R
authors.lastname: Beyaert
authors.affiliation: Institute for Medical Immunology, Free University of Brussels, Gosselies, Belgium.
authors.forename: Veronique
authors.initials: V
authors.lastname: Flamand
authors.affiliation: Centre for Cell Signaling, Barts Institute of Cancer, Queen Mary, University of London, London, UK.
authors.forename: Bart
authors.initials: B
authors.lastname: Vanhaesebroeck
mesh_terms: D000818:Animals; D002154:Calpain / Q000494:pharmacology; D002451:Cell Compartmentation / Q000276:immunology; D002462:Cell Membrane / Q000187:drug effects / Q000235:genetics / Q000276:immunology; D002478:Cells, Cultured; D058543:Class Ia Phosphatidylinositol 3-Kinase / Q000235:genetics / Q000276:immunology*; D003713:Dendritic Cells / Q000166:cytology / Q000187:drug effects / Q000276:immunology*; D011992:Endosomes / Q000187:drug effects / Q000235:genetics / Q000276:immunology; D015870:Gene Expression / Q000187:drug effects / Q000276:immunology; D016899:Interferon-beta / Q000096:biosynthesis / Q000276:immunology; D016753:Interleukin-10 / Q000096:biosynthesis / Q000276:immunology; D007527:Isoenzymes / Q000235:genetics / Q000276:immunology; D008070:Lipopolysaccharides / Q000494:pharmacology; D008562:Membrane Glycoproteins / Q000235:genetics / Q000276:immunology; D051379:Mice; D018345:Mice, Knockout; D018123:Receptors, Interleukin / Q000235:genetics / Q000276:immunology; D017472:Receptors, Interleukin-1 / Q000235:genetics / Q000276:immunology; D012772:Shock, Septic / Q000235:genetics / Q000276:immunology; D015398:Signal Transduction / Q000187:drug effects / Q000235:genetics / Q000276:immunology*; D051197:Toll-Like Receptor 4 / Q000235:genetics / Q000276:immunology*
chemical_list: D007527:Isoenzymes; D008070:Lipopolysaccharides; D008562:Membrane Glycoproteins; D018123:Receptors, Interleukin; D017472:Receptors, Interleukin-1; C499045:TIRAP protein, mouse; C476416:Ticam2 protein, mouse; C493487:Tlr4 protein, mouse; D051197:Toll-Like Receptor 4; D016753:Interleukin-10; D016899:Interferon-beta; D058543:Class Ia Phosphatidylinositol 3-Kinase; D002154:Calpain