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Nat Immunol. 2012 Nov;13(11):1045-1054. doi: 10.1038/ni.2426. Epub 2012 Sep 30.

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

Author information

Centre for Cell Signaling, Barts Institute of Cancer, Queen Mary, University of London, London, UK.
Institute for Medical Immunology, Free University of Brussels, Gosselies, Belgium.
Division of Cell and Molecular Biology, Centre for Molecular Microbiology and Infection, Imperial College London, London, UK.
Department for Molecular Biomedical Research, Unit of Molecular Signal Transduction in Inflammation, VIB, Ghent, Belgium.
Department of Biomedical Molecular Biology, Ghent University, Ghent, Belgium.
Contributed equally

Erratum in

  • Nat Immunol. 2013 Aug;14(8):877. Berenjeno-Martin, Inma [corrected to Berenjeno, Inma M].


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.

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