Journal article
The p110δ isoform of the kinase PI(3)K controls the subcellular compartmentalization of TLR4 signaling and protects from endotoxic shock
E Aksoy, S Taboubi, D Torres, S Delbauve, A Hachani, MA Whitehead, WP Pearce, I Berenjeno-Martin, G Nock, A Filloux, R Beyaert, V Flamand, B Vanhaesebroeck
Nature Immunology | Published : 2012
DOI: 10.1038/ni.2426
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 signal..
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Awarded by Universiteit Gent
Funding Acknowledgements
We thank R. Medzhitov (Yale University) for expression vectors encoding GST-TIRAP, GFP-TIRAP and GST-TIRAP-4x; S. Akira (Osaka University) and L. O'Neill (Trinity College, Dublin) for TLR4-, MyD88-, TRIF- or TIRAP-deficient mice; L. Stephens (Babraham Institute) for SHIP-1-deficient mice; L. Baud (Hopital Tenon) for mice with transgenic expression of calpastatin; G. Schiavo (London Cancer Research Institute) for the 2C11 mouse monoclonal antibody to PtdIns(4,5)P<INF>2</INF>; T. Kinashi (Kyoto University) for the 5' Myc membrane-targeted version of p110 delta in the pMX-neo vector; T. Maffucci (Queen Mary, University of London) for GST-PLC-delta-PH and GST-Akt-PH; H. Stenmark (Oslo University Hospital) for GST-Hrs-FYVE; D. Gray (University of Edinburgh) for the XL-60 cell line; and B. Manoury, N. Leslie and members of the Centre for Cell Signalling for comments. Supported by the European Union Marie Curie (IEF-041713 to E.A. and IEF-274749 to S.T); the European Molecular Biology Organization (ALTF 1083-2007 to E.A.); the Fondation ARC pour la Recherche sur la Cancer (SAE P2009); the Fund for Scientific Research Flanders; the Hercules Foundation and University of Ghent Multidisciplinary Research Partnership (for work in the laboratory of R.B.); the European Union Marie Curie International Graduate Program in Molecular Medicine (M.A.W.); and Cancer Research UK (C23338/A10200), the Ludwig Institute for Cancer Research and Queen Mary University of London (for work in the laboratory of B.V.).