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

(2012) NATURE IMMUNOLOGY. 13(11). p.1045-1054
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Ghent researchers on unfolded proteins in inflammatory disease (GROUP-ID)
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Ghent researchers on unfolded proteins in inflammatory disease (GROUP-ID)
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 p110 delta 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 p110 delta 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-beta). In line with that altered signaling output, p110 delta-deficient mice showed enhanced endotoxin-induced death. Thus, by controlling the 'topology' of TLR4 signaling complexes, p110 delta balances overall homeostasis in the TLR4 pathway.
Keywords
IIFN PRODUCTION, DENDRITIC CELLS, MEMBRANE FISSION, PLASMA-MEMBRANE, I INTERFERON, RECEPTOR, LIPOPOLYSACCHARIDE, PATHWAY, MICE, MAMMALIAN TARGET

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Citation

Please use this url to cite or link to this publication:

Chicago
Aksoy, Ezra, Salma Taboubi, David Torres, Sandrine Delbauve, Abderrahman Hachani, Maria A Whitehead, Wayne P Pearce, et al. 2012. “The P110δ Isoform of the Kinase PI(3)K Controls the Subcellular Compartmentalization of TLR4 Signaling and Protects from Endotoxic Shock.” Nature Immunology 13 (11): 1045–1054.
APA
Aksoy, E., Taboubi, S., Torres, D., Delbauve, S., Hachani, A., Whitehead, M. A., Pearce, W. P., et al. (2012). The p110δ isoform of the kinase PI(3)K controls the subcellular compartmentalization of TLR4 signaling and protects from endotoxic shock. NATURE IMMUNOLOGY, 13(11), 1045–1054.
Vancouver
1.
Aksoy E, Taboubi S, Torres D, Delbauve S, Hachani A, Whitehead MA, et al. The p110δ isoform of the kinase PI(3)K controls the subcellular compartmentalization of TLR4 signaling and protects from endotoxic shock. NATURE IMMUNOLOGY. 2012;13(11):1045–54.
MLA
Aksoy, Ezra, Salma Taboubi, David Torres, et al. “The P110δ Isoform of the Kinase PI(3)K Controls the Subcellular Compartmentalization of TLR4 Signaling and Protects from Endotoxic Shock.” NATURE IMMUNOLOGY 13.11 (2012): 1045–1054. Print.
@article{3060838,
  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 p110 delta 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 p110 delta 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-beta). In line with that altered signaling output, p110 delta-deficient mice showed enhanced endotoxin-induced death. Thus, by controlling the 'topology' of TLR4 signaling complexes, p110 delta balances overall homeostasis in the TLR4 pathway.},
  author       = {Aksoy, Ezra and Taboubi, Salma and Torres, David and Delbauve, Sandrine and Hachani, Abderrahman and Whitehead, Maria A and Pearce, Wayne P and Berenjeno-Martin, Inma and Nock, Gemma and Filloux, Alain and Beyaert, Rudi and Flamand, Veronique and Vanhaesebroeck, Bart},
  issn         = {1529-2908},
  journal      = {NATURE IMMUNOLOGY},
  keyword      = {IIFN PRODUCTION,DENDRITIC CELLS,MEMBRANE FISSION,PLASMA-MEMBRANE,I INTERFERON,RECEPTOR,LIPOPOLYSACCHARIDE,PATHWAY,MICE,MAMMALIAN TARGET},
  language     = {eng},
  number       = {11},
  pages        = {1045--1054},
  title        = {The p110\ensuremath{\delta} isoform of the kinase PI(3)K controls the subcellular compartmentalization of TLR4 signaling and protects from endotoxic shock},
  url          = {http://dx.doi.org/10.1038/ni.2426},
  volume       = {13},
  year         = {2012},
}

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