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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

1
Centre for Cell Signaling, Barts Institute of Cancer, Queen Mary, University of London, London, UK.
2
Institute for Medical Immunology, Free University of Brussels, Gosselies, Belgium.
3
Division of Cell and Molecular Biology, Centre for Molecular Microbiology and Infection, Imperial College London, London, UK.
4
Department for Molecular Biomedical Research, Unit of Molecular Signal Transduction in Inflammation, VIB, Ghent, Belgium.
5
Department of Biomedical Molecular Biology, Ghent University, Ghent, Belgium.
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Contributed equally

Erratum in

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

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.

PMID:
23023391
PMCID:
PMC4018573
DOI:
10.1038/ni.2426
[Indexed for MEDLINE]
Free PMC Article

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