Journal article

The p110 delta isoform of the kinase PI(3)K controls the subcellular compartmentalization of TLR4 signaling and protects from endotoxic shock

Ezra Aksoy, Salma Taboubi, David Torres, Sandrine Delbauve, Abderrahman Hachani, Maria A Whitehead, Wayne P Pearce, Inma Berenjeno-Martin, Gemma Nock, Alain Filloux, Rudi Beyaert, Veronique Flamand, Bart Vanhaesebroeck

Nature Immunology | NATURE PUBLISHING GROUP | Published : 2012

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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University of Melbourne Researchers

Grants

Awarded by European Union


Awarded by European Molecular Biology Organization


Awarded by Fondation ARC pour la Recherche sur la Cancer


Awarded by Cancer Research UK


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.).