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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.

par Aksoy, Ezra ;Taboubi, Salma;Torres, David ;Delbauve, Sandrine ;Hachani, Abderrahman ;Whitehead, Maria A;Pearce, Wayne P;Berenjeno-Martin, Inma;Nock, Gemma;Filloux, Alain;Beyaert, Rudi;Flamand, Véronique ;Vanhaesebroeck, Bart
Référence Nature immunology, 13, 11, page (1045-1054)
Publication Publié, 2012

Article révisé par les pairs

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Résumé :

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.