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PMID: 23023391 Published · ppublish English Journal Article Research Support, Non-U.S. Gov't

The p110δ isoform of the kinase PI(3)K controls the subcellular compartmentalization of TLR4 signaling and protects from endotoxic shock.

Nature immunology ·Vol. 13 ·No. 11 ·2012-11-00 ·Pages 1045-1054

Aksoy E, Taboubi S, Torres D, Delbauve S, Hachani A, Whitehead MA, Pearce WP, Berenjeno IM, Nock G, Filloux A, Beyaert R, Flamand V, Vanhaesebroeck B

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.

MeSH Terms
Animals Calpain/pharmacology Cell Compartmentation/immunology Cell Membrane/drug effects,genetics,immunology Cells, Cultured Class Ia Phosphatidylinositol 3-Kinase/genetics,immunology Dendritic Cells/cytology,drug effects,immunology Endosomes/drug effects,genetics,immunology Gene Expression/drug effects,immunology Interferon-beta/biosynthesis,immunology Interleukin-10/biosynthesis,immunology Isoenzymes/genetics,immunology Lipopolysaccharides/pharmacology Membrane Glycoproteins/genetics,immunology Mice Mice, Knockout Receptors, Interleukin/genetics,immunology Receptors, Interleukin-1/genetics,immunology Shock, Septic/genetics,immunology Signal Transduction/drug effects,genetics,immunology Toll-Like Receptor 4/genetics,immunology
Chemicals
Isoenzymes Lipopolysaccharides Membrane Glycoproteins Receptors, Interleukin Receptors, Interleukin-1 TIRAP protein, mouse Ticam2 protein, mouse Tlr4 protein, mouse Toll-Like Receptor 4 Interleukin-10 Interferon-beta Class Ia Phosphatidylinositol 3-Kinase Calpain
Authors & Affiliations
13 authors, click to expand affiliations / ORCID
Aksoy Ezra
Centre for Cell Signaling, Barts Institute of Cancer, Queen Mary, University of London, London, UK.
Taboubi Salma
Centre for Cell Signaling, Barts Institute of Cancer, Queen Mary, University of London, London, UK.
Torres David
Institute for Medical Immunology, Free University of Brussels, Gosselies, Belgium.
Delbauve Sandrine
Institute for Medical Immunology, Free University of Brussels, Gosselies, Belgium.
Hachani Abderrahman
Division of Cell and Molecular Biology, Centre for Molecular Microbiology and Infection, Imperial College London, London, UK.
Whitehead Maria A
Centre for Cell Signaling, Barts Institute of Cancer, Queen Mary, University of London, London, UK.
Pearce Wayne P
Centre for Cell Signaling, Barts Institute of Cancer, Queen Mary, University of London, London, UK.
Berenjeno Inma M
Centre for Cell Signaling, Barts Institute of Cancer, Queen Mary, University of London, London, UK.
Nock Gemma
Centre for Cell Signaling, Barts Institute of Cancer, Queen Mary, University of London, London, UK.
Filloux Alain
Division of Cell and Molecular Biology, Centre for Molecular Microbiology and Infection, Imperial College London, London, UK.
Beyaert Rudi
Department for Molecular Biomedical Research, Unit of Molecular Signal Transduction in Inflammation, VIB, Ghent, Belgium. | Department of Biomedical Molecular Biology, Ghent University, Ghent, Belgium.
Flamand Veronique
Institute for Medical Immunology, Free University of Brussels, Gosselies, Belgium.
Vanhaesebroeck Bart
Centre for Cell Signaling, Barts Institute of Cancer, Queen Mary, University of London, London, UK.
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Article Info
Journal
Nature immunology
Abbr.
Nat Immunol
ISSN
1529-2916
DOI
10.1038/ni.2426
Published
2012-11-00
Epub
2012-00-30
Pages
1045-1054
Language
English
Region
United States
NLM ID
100941354
PMCID
PMC4018573
Subset
IM
Grants
Wellcome Trust · 091939 · United Kingdom
Cancer Research UK · C23338/A10200 · United Kingdom
Corrections
ErratumIn
-
CommentIn
PMID: 23059427
CommentIn
PMID: 23080196
External Links
PubMed source DOI: 10.1038/ni.2426 PMC Full Text View journal details
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